HLA matching enhances long-term renal graft survival but does not relate to acute rejection.

Forty patients with end-stage chronic renal failure received living donor renal grafts, matched at more than 1 HLA haplotype, over the last 25 years. Of these grafts, 33 were first and 7 were second grafts. All recipients received prophylactic corticosteroids. Thirty-four also received prophylactic azathioprine, and 6, prophylactic cyclosporine. Acute rejection occurred in 65% (11/17) of non-cyclosporine treated grafts when the recipient was given 5 or fewer units of blood preoperatively, but in only 18% (3/17) when more than 5 units were given. High-dose steroid therapy reversed the acute rejection each time. Chronic rejection occurred in 2 grafts. Irreversible rejection did not occur in any second graft. Chronic glomerulonephritis, possibly due to recurrent disease, occurred in 1 graft. Five grafts have been lost, 1 each from technical and immunosuppressive complications, and 3 from incidental death. The 1-year actuarial graft survival rate is 95% and the 10-year rate 84%. All surviving patients lead normal lives without significant health restriction, and employ minimal medication. It is postulated that: 1) acute cellular rejection is HLA-independent, and chronic rejection is HLA-dependent, and 2) hyperacute and chronic rejection are related and are parts of a spectrum of humoral immunity.

HLA-identity--long-term renal graft survival, acute vascular, chronic vascular, and acute interstitial rejection.

The object is analysis of the impact of acute and chronic rejection on long-term function in HLA-identical renal transplants performed from 1967 to 1995 by the Saskatchewan Renal Transplant Unit. Forty-eight grafts in 46 patients were studied, of which 39 were first and nine second grafts. Forty-two were for primary and six for secondary renal disease. Thirty-five received azathioprine/prednisone prophylaxis, and 13 received cyclosporine/prednisone with/without azathioprine. Ten-year all graft actuarial survival was 84%, 10-year actuarial graft survival in patients with primary renal disease 90%, and with subsequent graft after first HLA graft failed 97.5%, for age-matched population 98.5% (P=NS). Overall death rate was 8.7% (4/46); in secondary renal disease patients 50% (3/6); in primary renal disease patients 2.5% (1/40, P=0.004). All (9/9) HLA-identical second grafts functioned. Acute rejection with azathioprine/prednisone prophylaxis occurred in 55% (9/17) of grafts treated with <6 pre-graft blood transfusions, with the same prophylaxis but >5 units in 12% (2/16, P=0.015), and with cyclosporine prophylaxis in 13% (2/15, P=0.021). Pulse steroids alone reversed all acute rejection. Grafts failed in 6.2% (3/48), all in primary renal disease patients and one from technical one noncompliance, and one chronic rejection. Graft cost/patient/year amortized over 9 years is $3,855 and comparable dialysis cost would be $35,650; cost for all patients on dialysis for 9 years would be $11,293,320 while comparable graft cost was 1,221,418, a savings of 89.2%. Our conclusions are that HLA-identity associates with the following: (1) a 10-year actuarial survival in primary renal disease that equals that of the age-matched population, (2) uniform success in repeat grafts, (3) virtual absence of chronic rejection despite a high incidence of acute rejection in azathioprine/prednisone grafts that (4) always reversed on pulse steroids, and (5) a cost reduction for grafting of 93.2% compared with dialysis therapy.

Alloantigen-blocking antibodies in sera from highly sensitized uremic patients: antibody class and relationship with lymphocytotoxins.

BACKGROUND: Previously, we identified an antimitogenic IgG antibody separated from sera of patients with known kidney transplant chronic rejection. This antibody inhibits individual patients' own unprimed T helper cell responses to alloantigens as well as a third-party mixed lymphocyte response, but does not inhibit autologous unprimed T helper cell proliferation to adherent anti-CD3 antibody. We suggest that the mechanism of inhibitory action is allogeneic-dependent. METHODS: We used a series of similar experimental designs to test the presence of this antibody in uremic, sensitized patients and have studied its relationship to sensitization as defined by the presence of lymphocytotoxins in four uremic groups: highly sensitized with or without previous graft loss, moderately sensitized with or without graft loss, nonsensitized without previous graft loss, and nonsensitized with graft loss. RESULTS: (1) Sensitization is associated with the presence of a potent antibody that blocks primary mixed lymphocyte response. Primed cells are less susceptible to its antimitogenic action. (2) The blocking antibody activity is present only in sensitized patients who have IgG lymphocytotoxic activity against the same HLA class I antigens. (3) The blocking activity is unequal in the following order: IgG 3 > IgG 1 > IgG 2. (4) Although IgG 1 and 2 fractions contain lymphocytotoxic activity against HLA class I antigens, the IgG 3 fraction does not. CONCLUSIONS: The differential effect of IgG antibodies on naive and memory T cells may explain why humeral responses to alloantigens can be maintained in the presence of blocking antibodies.

Accuracy of oximetry with thermistor (OxiFlow) for diagnosis of obstructive sleep apnea and hypopnea.

OBJECTIVES: To evaluate the diagnostic accuracy for obstructive sleep apnea and hypopnea (OSAH) of the OxiFlow (OF) device which combines oximetry with recording of thermistor airflow. DESIGN & SETTING: Patients scheduled for overnight diagnostic polysomnography (PSG) were studied with OF either simultaneously during laboratory PSG (L-OF, n=86), at home on a separate night (H-OF, n=66), or both (n=55). PATIENTS: 97 patients with suspected OSAH, of whom 40 had OSAH defined as an apnea-hypopnea index (AHI) of more than 15 events per hour of sleep on PSG. INTERVENTIONS: NA. MEASUREMENTS & RESULTS: The automated respiratory disturbance index (RDI) generated by the OF software considerably underestimated the AHI by PSG for both L-OF and H-OF. Altering the parameters for hypopnea identification by the software did not improve this. Visual inspection of the computerized OF tracings added considerable diagnostic information, but a manual count of RDI during visual review overestimated AHI. For the identification of cases vs. non-cases of OSAH, receiver operating characteristic area-under-the-curve statistics ranged from 0.77-0.90 for L-OF and from 0.71-0.77 for H-OF. Combining automated analysis with subsequent visual inspection of OF tracings yielded an overall sensitivity of 86% and specificity of 74% for the diagnosis of OSAH during H-OF recordings. Analysis of potential technician time saved indicated a benefit from the use of OF. CONCLUSIONS: OF has diagnostic utility for the identification of OSAH. However, because of hardware and software limitations, it is unclear whether this device is superior to oximetry alone.

Protein malnutrition and decreased protein turnover in chronic renal allograft failure.

OBJECT: To define the longitudinal relationship of declining renal function to protein consumption and turnover in the failing renal allograft model of chronic renal failure. METHOD: The study group is our first eight consecutive cadaveric renal graft recipients who after attaining a normal creatinine clearance, then developed chronic renal failure. We analysed their urea and creatinine clearances (Cur, Ccr), serum urea (SU), urinary urea and creatinine (Ur, Ucr), serum albumin (SA), urinary protein (Upr), body weight (BW), and steroid dose. Steady state Uur is also dietary protein intake (DPI) and protein catabolic rate (PCR). Ucr measures body protein mass. Ucr/Uur measures the ratio of body protein mass to urea excretion. Mean follow-up 4.7 years, range 1.5-8.7 years. RESULTS: Mean changes: (1) Body weight (BW) rose from 56 to 65 and then fell to 61 kgms. (2) Cur fell 65 to 5 and Ccr 92 to 12 ml/min/70 kg. (3) Uur fell from 369 to 107 and Ucr from 16.8 to 9.5 mmols/day/70 kg. (4) Uur/Ucr indexed at 1:1 fell to 0.49. (5) SU rose from 8.8 to 34.9 mmol/1; SA fell from 36.1 to 31.0 gms/1; Upr rose from 1.4 to 2.3 gms/day. (6) Prednisone rose from 26 to 66 and then fell to 33 mgms/day. Correlations: (1) Cur and Uur(r = 0.99, p < 0.001). (2) Ccr and Uur (r = 0.99, p < 0.001). (3) Cur and Uur/Ucr (r = 0.88, p < 0.01) with a decelerating breakpoint at Cur 18 and Ccr 32 ml/min/70 kg (p < 0.01). (4) SU and Uur negatively (r = 0.90, p < 0.01. (5) Cur and SA albumin (r = 0.82, p < 0.05). (6) Cur and prednisone, Upr and SA do not correlate. CONCLUSIONS: In this model of chronic renal failure: (1) Renal function controls protein intake. (2) Body protein mass is relatively well preserved despite the decreased protein intake implying a decrease in the protein turnover rate and a consequent increase in body protein average age. (3) Protein malnutrition, protein ageing, and decreased protein turnover are likely pathophysiological reactions to chronic renal failure and may be part of the pathogenesis of chronic uremia.

Improved urea clearance raises the BUN in continuous peritoneal dialysis.

Cross-sectional studies in steady state dialysed chronic end-stage renal failure patients show urea clearance (Kt/V) and total urea excretion (protein catabolic rate) correlate positively. However, urea clearance is total urea excretion divided by BUN. Thus urea clearance and BUN relate reciprocally, and so their mathematical product (total urea excretion) is independent of clearance. As such clearance cannot also be a positive correlate of total excretion as demanded by the cross-sectional studies. Furthermore the clearance formula dictates that the positive urea clearance and total urea excretion correlation found in the cross-sectional studies can only occur if the increased urea clearance fails to reciprocally lower the BUN. Thus the relations of urea clearance, urea excretion, and BUN requires further definition. To so define we examine dialysis urea excretion, dialysis urea clearance, BUN, and serum albumin in 13 stabilized chronic uremics with minimal native renal function who are treated by continuous ambulatory peritoneal dialysis (CAPD). Urea clearance and BUN correlate positively (r = 0.62, p < 0.05) and both also correlate positively with dialytic urea excretion and (urea clearance r = 0.912, p < 0.001, BUN r = 0.88, p < 0.001). In addition dialytic urea excretion and serum albumin indexed to body size correlate positively (p < 0.05). Thus in the steady state urea clearance associates with both an increase in BUN and urea output. However the law of conservation of mass makes urea output is a function of protein intake. Thus increased clearance cannot directly increase such output, and so increased clearance must first increase intake but in doing so it increases the retention of the byproducts of enhanced intake, BUN and other protein metabolites, so leading to a paradox, the more removed, the more remains. These observations taken together suggest that in chronic uremia treated by continuous dialysis, elevation of the BUN may be a marker for an adequate restoration of protein metabolism if inadequate dialysis is excluded.

Variations in living donor graft rates by dialysis clinic: effect on outcome and cost of chronic renal failure therapy.

OBJECT: Examination of nephrology practice variations in living donor renal grafts to determine their influence on organ supply, quality, and cost of chronic renal failure therapy. MATERIALS: Saskatchewan chronic dialysis, cadaveric, and living donor renal grafts in 1983-1994 inclusive. RESULTS: Saskatchewan has three dialysis (I, II, III) and one transplant clinic. In the period the renal graft incidences/million population by these dialysis clinics by organ source were; Cadaveric: 23.1, 23.2, 21.1 (p = ns). Living: 5.4, 21.7, 8.3 (I or III vs II p < 0.000, I vs III p < 0.061). Total: 28.7, 44.7, 29.4. Living donor series A is 79 grafts in patients under age 60 with primary renal disease. Series B is 20 grafts in patients with secondary renal disease or over age 59. Series A ten-year actuarial patient survival is 92% and B 44%. Series A ten-year actuarial graft survival (including regrafts) is 77% and B 39%. Rehabilitation rate in patients with functioning grafts is 88.5%. Province-wide extension of the Clinic II living-donor graft rate in 1983-1994 would have produced 160 more renal grafts or 59% of those receiving chronic dialysis in 1994. The annual maintenance for a graft with the initial grafting cost taken over five years was $10,825 and the dialysis cost $40,100. CONCLUSIONS: (1) nephrology practice variations caused a 2.5-4.0-fold difference in living donor renal graft rates, indicating patient education by the attending nephrologist influences the living donor transplantation rate, (2) with such education the combined living donor and the cadaveric organ supply virtually meets graft demand, (3) living donor renal grafts yield a better quantity and quality of life and better cost control than dialysis with their annual cost being one-quarter that for dialysis.

Prevention of CAN graft loss in the medium term without HLA disparity reduction.

INTRODUCTION: This study compares the incidence of cadaveric graft failure from chronic allograft nephropathy in the medium term (1 to 5 years) using older and newer immunosuppressive regimens. The older regimen was established triple therapy and the newer regimen, almost universal replacement of azathioprine by mycophenolate. MATERIALS AND METHODS: In the older series, 76 (71 after death censoring) cadaveric renal grafts done from 1990 to mid-1996 in patients who survived for more than 1 year were analyzed. In the newer series, 49 (45 after death censoring) cadaveric grafts done 5 or more years ago in patients surviving 1 year were analyzed. In the older series, immunosuppression was combined steroids, cyclosporine, and azathioprine. In the newer series, mycophenolate replaced azathioprine in 85%, historically conventional immunosuppression was used in 7.5%, and miscellaneous in 7.5%. RESULTS: Cumulative deaths in years 1 to 5 with renal graft function were as follows: older series, 6.6% (5/76), newer 8.2% (4/49) (P = NS). In the older series, death-censored 1- to 5-year cumulative graft failure was 35.2% (24/71), newer series 4.4% (2/45) (chi-square 13.5, relative risk reduction 0.87 [0.51 to 0.97], P =.00021). ACE-inhibitor antihypertensive therapy was used in 25% (18/71) of the patients in the older series and in 53% (24/45) of patients in the newer series (chi-square 6.1, relative risk 1.8 [1.1 to 2.9], P =.01). CONCLUSION: Replacement of azathioprine with mainly myocophenolate in triple immunosuppression and enhanced use of ACE inhibitors are associated with near complete prevention (87%) of medium-term CAN graft failure, making death with graft function now the major cause of graft loss in this time.

The new role of the hospital emergency department.

The volume of medical services delivered within hospital emergency departments in the City of Saskatoon is increasing rapidly. These probably are not "new" medical services but rather represent a transfer of "old" services to the emergency departments from other sites where they were previously rendered. The visit to the emergency department is initiated more often by the patient than the doctor and once there the patient is treated in a relatively short period of time. The illnesses so managed do not have a diagnostic, therapeutic or prognostic uniformity but rather are characterized by their acute and totally unexpected onset. This acute and non-programmable nature of the illness makes it difficult to deliver the service in a physician's office where the appointment system prevails and efficiently deals with the great majority of his patients. Data to determine whether or not this is a desirable development have not yet been obtained but it is clear that in its present usage the emergency department must be thought of as a facility which not only provides exceptional diagnostic and therapeutic equipment but as one which also provides a treatment facility without prior appointment available at any hour of the day or night.

Doctor/Government fee negotiations in Canada.

The original medicare act, passed by a socialist government in Saskatchewan in 1962, ;invented' extra-billing and health care insurance premiums. Now the Canada Health Act seeks to ban extra-billing by penalizing provinces which reimburse patients who have been so billed. The patient, not the profession, loses. Yet the public's perception is that the government is acting in their best interests! This retrograde step takes Canada back to square one-premedicare Saskatchewan in 1962.

Late failure in cadaveric renal allografts.

Sixteen patients with renal cadaveric allografts who have survived for one year or longer are reported. The patients were analyzed from the standpoint of incidence, quantity and course of proteinuria in relation to renal function and the nature of the original disease.This analysis shows that proteinuria is progressive and is accompanied by a decline in renal function when the original disease is of an immune nature. This was not so in patients with non-immune original disease. These findings suggest that recurrence of original disease plays an important role in late failure of cadaveric renal allografts.

Clinical value of cadaveric renal homotransplantation.

Cadaveric renal transplantation was found to be potentially applicable to 80% of a uremic population as observed over a six-year period. Death prior to presentation of a donor kidney occurred in 25%, 40% have received transplants and 15% are awaiting transplantation. Transplantation resulted in restoration of near normal renal function and homograft survival rates of 45% at one year, 40% at two years and 17% at four years. Failure of the therapeutic procedure resulted more often from death of the patient than from failure of the donor organ. Patient death was most frequently ascribed to complications of the immunosuppressive therapy, but cardiovascular accidents were also a significant cause. Early renal failure was due to hyperacute or acute rejection, while the cause of late renal failure remains unproved. Re-transplantation was effective treatment for late failure and, as a result, the four-year patient survival is nearly 40% compared to four-year initial kidney survival of 17%.

Early acute rejection in renal homotransplantation. Angiographic-pathologic correlation.

Early acute rejection occurs between two and ten days after renal homotransplantation and has been recognized in eight of 156 renal transplants. Four of the eight patients developed spontaneous renal rupture unrelated to biopsies. Pathologically, there was acute passive congestion with areas of tubular necrosis, venous thrombi and perivenous lymphoplasia. Glomerular and arterial immunogenic injury was slight. Radiologically, the kidneys were enlarged with stretching of the interlobar and segmental arteries, decreased peripheral filling and a homogeneous nephrogram. Renal vein filling defects were a frequent feature.

Experiences with high doses of furosemide in renal disease and resistant edematous states.

Six cases of edema, three due to the nephrotic syndrome, one to congestive heart failure and two to chronic renal failure, are reported in which furosemide was administered in oral doses higher than those usually prescribed (up to 720 mg. a day), in order to obtain a satisfactory diuresis. In one case of severe prerenal failure secondary to cardiogenic shock and in one case of acute tubular necrosis secondary to hypotension at the time of operation, intravenous doses up to 990 and 1400 mg. per day respectively were able to reverse the oliguria. In eight additional patients who were on chronic hemodialysis, furosemide was administered to the amount of 1000 mg. per day orally in divided doses for two weeks, and produced a moderate diuretic response.The use of high doses of furosemide in edema and renal failure resistant to the usual therapeutic measures appears to be safe and effective.

Early acute rejection of renal homografts: a characteristic clinical syndrome.

Seven of 74 patients with early functioning cadaveric renal homografts developed acute oliguric renal failure after the second but before the ninth day post-transplantation. The syndrome characteristically begins with an abrupt and simultaneous decrease in creatinine clearance, urine volume and urine sodium concentration. After a variable period and despite a reduction in immunosuppressive therapy, a diuretic phase ensues and renal function is restored. Complications associated with the syndrome include groin hematoma, pulmonary edema and renal rupture with shock. Renal rupture does not require nephrectomy: if the hemorrhage is controlled, the transplanted organ will resume function. Angiographic studies show normal nephrograms, stretched arterial vasculature and filling defects in the veins. Percutaneous renal biopsy shows interstitial edema and hemorrhage, venous congestion and tubular necrosis. Evidence is presented to support the hypothesis that this is a form of rejection occurring as the result of injury to the renal venous system.

Antihypertensives and myocardial infarction risk: the modifying effect of history of drug use.

PURPOSE: Confounding by indication is common in observational studies of outcomes that treatment is intended to affect. In light of the stepped-care approach to hypertension management, we reexamined the controversy around myocardial infarction (MI) risk in relation to antihypertensive agents by considering past drug history both as a confounder and as an effect modifier. METHODS: Case-control design nested within a cohort of 19,501 adults initiating therapy with angiotensin-converting enzyme inhibitors (ACEI), calcium channel blockers (CCB) or beta-blockers in Saskatchewan (1990-93) and followed up to 1997. MI cases were identified using death certificates and hospital discharge diagnoses (ICD-9,410). Four controls were matched to each case to account for duration and timing of follow-up. RESULTS: 812 MI cases were identified, of which 26% were fatal. At first, current use of CCB and ACEI (versus beta-blockers) appeared to be associated with an increased risk of MI (RR = 2.2; 95% CI = 1.8-2.7 and RR = 1.3; CI = 1.0-1.6 respectively). Adjustment for drug use history attenuated both associations (RR = 1.6; CI = 1.1-2.2 and RR = 1.0; CI = 0.7-1.4). Moreover, the risk for CCB use disappeared when restricted to patients who had already used these agents in the past (RR = 1.1; CI = 0.77-1.7) whereas a high risk of MI for ACEI was found in digoxin users (RR = 9.4; CI = 3.2-27.5). CONCLUSION: Past drug history can be both a confounder and an effect modifier in observational studies. We found adjustment for medication history to attenuate the associations between antihypertensive agents and MI risk. In addition, the estimates significantly varied across drug history profiles thus suggesting the presence of preferential prescribing of specific drug classes to high-risk patients.