HLA B27 in Ankylosing Spondylitis: Differences in Frequency and Relative Risk in American Blacks and Caucasians.

Twenty-eight HLA alleles of the A and B loci were determined in 23 American Blacks and 50 Caucasians with primary ankylosing spondylitis (AS). The prevalence of HLA B27 was significantly increased in American Black patients (48 per cent) vs Black controls (two per cent), but was much less than the 94 per cent found in Caucasian patients (controls eight per cent). The lower prevalence of B27 in American Black patients vs Caucasian patients was significant (p < 0.001), and indicated that susceptibility to AS is not as closely associated with B27 in Blacks as in Caucasians. No other HLA antigen was significantly associated with AS in either racial group. Among B27 positive individuals, the relative risk of developing AS was significantly lower in American Blacks than in Caucasians. These data indicate that for diagnostic purposes, the absence of B27 is less important in ruling out AS in Blacks than in Caucasians.

Decreased total CD19⁺ B lymphocytes and the occurrence of monoclonal proteins are frequent in ultra-long (30 to 44-year) renal transplant recipients: implications for allograft and patient survival.

BACKGROUND: The B-cell signature of tolerance in kidney transplant patients receiving no immunosuppression includes a significant increase in total CD19(+) B cells. METHODS: We evaluated kidney transplant recipients with primary functioning allografts for 30-44 years receiving minimal immunosuppression to determine whether they have the same CD19(+) B-cell changes or unusual serologic findings. We included 44 kidney allograft recipients with a graft functioning for 30-44 years, who were treated primarily with minimal prednisone and azathioprine. Twenty-four other recipients whose allografts functioned >30 years were unable to be studied (unable to travel, lost to follow-up, deceased). RESULTS: The number and percentage of CD19(+) B cells were depressed in 70.5% (31/44) and 81.8% (36/44), respectively, of these 44 ultra-long renal transplant recipients. The other major finding was identification by immunofixation of a monoclonal protein (MP) in 45.5% (20/44) of these same recipients. Among the 26 patients with good or excellent renal function (estimated glomerular filtration rate [eGFR] ≥ 45 mL/min/1.73 m(2); group 1), 12 had a single MP for >1 year, 13 no MP, and 1 a double MP. Conversely, in the 18 patients with fair/failed function (eGFR <40 mL/min/1.73 m(2) in 8, or end-stage renal disease after 30 years in 10; group 2), 3 had a transient single MP or free light chains only, 11 no MP, and 4 a double MP (P = .0425). CONCLUSIONS: These data reveal that about three quarters of ultra-long renal transplant recipients had low CD19(+) B cells, compared with the elevated B-cell signature reported in tolerant kidney recipients, and nearly half (45.5%) had a serum MP that was not associated with low B cells or mortality. Those with a stable single MP had better graft function.

Assessing glomerular filtration rate by estimation equations in kidney transplant recipients.

Surveillance of glomerular filtration rate (GFR) is crucial in the management of kidney transplant recipients. With special emphasis on serum creatinine (SCr) calibration assay, we assessed the performance of estimation equations as compared to iothalamate GFR (iGFR) in 209 patients using the modification of diet in renal disease (MDRD), Nankivell and Cockcroft-Gault methods. Fifty-five percent of patients were treated with a calcineurin inhibitor (CNI) and all were taken trimethroprim-sulfametoxazole at the time of SCr measurement. The mean iGFR was 44 +/- 26 mL/min/1.73 m2. The MDRD equation showed a median difference of 0.9 mL/min/1.73 m2 with 53% of estimated GFR within 20% of iGFR. Median differences were 7.5 and 7.0 mL/min/1.73 m2 for Nankivell and Cockcroft-Gault formulas, respectively. The accuracy of the Nankivell and Cockcroft-Gault formulas was such that only 38% and 37% of estimations, respectively, fell within 20% of iGFR. The performance of all equations was not uniform throughout the whole range of GFR, with some deterioration at the extremes of GFR levels. In addition, good performance of the MDRD equation was seen in subjects taking CNI. In conclusion, the overall performance of the MDRD equation was superior to the Nankivell and Cockcroft-Gault formulas in renal transplant recipients including subjects treated with CNI.

Long-term renal transplantation. Recent successes and new problems.

There has been continued improvement in preventing early biopsy-proved acute rejections and increasing 1-year allograft success rates, and, after some delay, the conditional half-life of grafts. Beneath these impressive achievements are several troubling concerns: unrecognized subclinical rejections; the emergence of acute and chronic humoral rejection; the different effect of certain acute rejections on the development of chronic rejection; the possibility that the current improvements in reducing early acute rejection may not be translated into longer half-life for the graft unless important adjunctive therapy is included. The use of cyclosporine (CSA) has been reshaped by lower dosing, conversion and avoidance protocols, C2 blood level monitoring, availability of generics, and application to non-transplant immunologically-mediated renal diseases. The enigma of chronic allograft nephropathy (CAN) unfortunately still remains, but recent studies on the effects of hypomagnesemia are provocative. The actual cohort of truly long-term renal transplant successes is providing remarkable insights into the way such grafts and their recipients achieve 30-year success. More than half of these patients have experienced early acute rejections (even Banff II and III). Somewhat contrary to expectations, these recipients usually do not have subnormal levels of CD4+ and CD8+ lymphocytes. However, they are typically B cell depleted, a condition that may protect them from late humoral rejection. Future directions will likely lead to the inclusion of important adjunctive agents having secondary anti-proliferative and anti-fibrogenic capabilities. Because chronic injury to renal allografts, as well as the dominant complications of renal transplantation such as cardiovascular disease and skin cancers, are woven together by a common theme of excessive proliferative activity, albeit of different cell types, long-term therapy will be directed at both protecting the allograft and the allograft recipient by incorporating as long-term therapy selected anti-proliferative agents that could include inhibitors of the renin-angiotensin-aldosterone system, statins, sirolimus, mycophenolic acid and leflunomide.

Renal outcome 25 years after donor nephrectomy.

PURPOSE: The extended outcome after kidney donation has been a particular concern ever since the recognition of hyperfiltration injury. Few published reports have examined donor renal outcome after 20 years or greater. Kidney transplantation has been performed at the Cleveland Clinic Foundation since 1963, at which there is extensive experience with live donor transplantation. We assess the impact of donor nephrectomy on renal function, urinary protein excretion and development of hypertension postoperatively to examine whether renal deterioration occurs with followup after 20 years or greater. MATERIALS AND METHODS: From 1963 to 1975, 180 live donor nephrectomies were performed at the Cleveland Clinic. We attempted to contact all patients to request participation in our study. Those 70 patients who agreed to participate in the study were mailed a package containing a 24-hour urine container (for assessment of creatinine, and total protein and albumin), a vial for blood collection (for assessment of serum creatinine) and a medical questionnaire. All specimens were returned to and processed by the Cleveland Clinic medical laboratories. Blood pressure was taken and recorded by a local physician. A 24-hour creatinine clearance and the Cockcroft-Gault formula were used to estimate renal function, and values were compared with an age adjusted glomerular filtration rate for a solitary kidney. RESULTS: Mean patient followup was 25 years. The 24-hour urinary creatinine clearance decreased to 72% of the value before donation. For the entire study cohort serum creatinine and systolic blood pressure after donation were significantly increased compared with values before, although still in the normal range. The overall incidence of hypertension was comparable to that expected in the age matched general population. There was no gender or age difference (younger or older than 50 years) for 24-hour urinary creatinine clearance, or change in serum creatinine before or after donation. Urinary protein and albumin excretion after donation was significantly higher in males compared with females. There were 13 (19%) subjects who had a 24-hour urinary protein excretion that was greater than 0.15 gm./24 hours, 5 (7%) of whom had greater than 0.8. No gender difference was noted in blood pressure, and there were no significant changes in diastolic pressure based on gender or age. CONCLUSIONS: Overall, renal function is well preserved with a mean followup of 25 years after donor nephrectomy. Males had significantly higher protein and albumin excretion than females but no other clinically significant differences in renal function, blood pressure or proteinuria were noted between them or at age of donation. Proteinuria increases with marginal significance but appears to be of no clinical consequence in most patients. Patients with mild or borderline proteinuria before donation may represent a subgroup at particular risk for the development of significant proteinuria 20 years or greater after donation. The overall incidence of proteinuria in our study is in the range of previously reported values after donor nephrectomy.

Laparoscopic bilateral synchronous nephrectomy for autosomal dominant polycystic kidney disease: the initial experience.

PURPOSE: We report our experience with laparoscopic bilateral synchronous nephrectomy for giant symptomatic autosomal dominant polycystic kidney disease (ADPKD) and compare outcome data with open bilateral nephrectomy. MATERIALS AND METHODS: Since March 1998, 10 patients underwent bilateral synchronous laparoscopic nephrectomy for giant symptomatic ADPKD. A 3 port retroperitoneal laparoscopic approach was used to secure the renal hilum and mobilize the kidney. Intact specimen extraction was performed through a midline infraumbilical extraperitoneal incision. The patient was then repositioned for the contralateral retroperitoneoscopic nephrectomy, with the second specimen also delivered through the same infraumbilical incision. Data were retrospectively compared with 10 patients who had undergone bilateral synchronous open nephrectomy for ADPKD between 1981 and 1992. RESULTS: Patients in the laparoscopic and open groups were comparable in regard to age (53 versus 47 years, p = 0.54) and Anesthesiologist Society of America class (3 versus 3, p = 0.84) but patients in the laparoscopic group were significantly more obese (body mass index 35.9 versus 23.8, p = 0.02). For comparable total specimen weights (3 versus 3 kg, p = 0.69) surgical time was longer in the laparoscopic group (4.4 versus 3.8 hours, p = 0.007). However, the laparoscopic group was superior in regard to blood loss (150 versus 325 cc, p = 0.05), postoperative requirement of nasogastric tube (10% versus 100%, p = 0.0001), narcotic analgesics (34.2 versus 120.4 mg. morphine sulfate equivalent, p = 0.03) and hospital stay (1.5 versus 9 days, p = 0.004). Complications occurred in 5 patients (50%) in the laparoscopic group and 4 (40%) in the open group (p = 0.66). No laparoscopic case was converted to open surgery. CONCLUSIONS: Synchronous bilateral retroperitoneal laparoscopic nephrectomy for giant symptomatic adult polycystic kidney disease is feasible, safe and efficacious, and can be performed either before or after renal transplantation. Compared to open surgery, the laparoscopic approach results in significantly shorter hospital stay, decreased morbidity and quicker recovery. Laparoscopy is currently our technique of choice in this setting.

Significant post-transplant hypogammaglobulinemia in six heart transplant recipients: an emerging clinical phenomenon?

BACKGROUND: The recent development of powerful agents such as mycophenolate mofetil and tacrolimus has altered current regimens for the prevention and treatment of allograft rejection. Questions have been raised about these newer regimens in terms of susceptibility to opportunistic infections and effects on host defenses. Severe hypogammaglobulinemia has been infrequently described in solid organ transplant recipients, but has been recently noted in six heart transplant recipients at one center, of whom five were receiving a combination of tacrolimus, mycophenolate mofetil, and prednisone. METHODS: Case summaries of six recent heart transplant recipients with total immunoglobulin G (IgG) levels of less than 310 mg/dl, five of whom had cytomegalovirus (CMV) infection and three of whom had multiple infections including Nocardia, invasive Trichophyton, and Acinetobacter bacteremia. Previous literature was reviewed with the aid of a Medline search using the search terms hypogammaglobulinemia; kidney, liver, heart, lung, and organ transplantation; mycophenolate mofetil; tacrolimus; cyclosporine; azathioprine; and nocardiosis. RESULTS: We here report six cardiac transplant recipients seen over a period of one year who were found to have immunoglobulin G levels of 310 mg/dl or below (normal: 717-1400 mg/dl). The first five patients were diagnosed because of evaluation for infections; the sixth, who was asymptomatic with an IgG level of 175, was found during screening for hypogammaglobulinemia instituted as a result of these first five patients. All six patients had received steroid pulses for rejection; all received mycophenolate mofetil; and 5/6 had been switched from cyclosporine to tacrolimus because of steroid-resistant rejection. Transient neutropenia (absolute neutrophil count less than 1000) was observed in 2/6; 3/6 had received OKT3 therapy for refractory rejection. These six patients were treated with a combination of antimicrobials, immunoglobulin replacement, and decrease in immunosuppressive therapy. CONCLUSION: The finding of unexpected hypogammaglobulinemia and concomitant infectious complications in six heart transplant recipients highlights a possible complication in a subset of patients receiving newer immunosuppressive agents. A larger prospective study is underway to determine risk factors for development of post-transplant hypogammaglobulinemia and to assess pre-transplant immune status of these recipients. Monitoring of immunoglobulin levels in high-risk patients receiving intensified immunosuppressive therapy for rejection may help to prevent infectious complications.

Chronic viral hepatitis in renal transplant recipients with allografts functioning for more than 20 years.

BACKGROUND: The impact of infection with hepatotropic viruses (hepatitis B virus [HBV] and hepatitis C virus [HCV]) on morbidity and mortality, and allograft function in renal transplant recipients with allografts functioning for >20 years is not known. METHODS AND RESULTS: Seventy-nine of 511 renal transplants performed at the Cleveland Clinic Foundation from January 1963 to January 1978 are known to have functioned for at least 20 years (level 5A). Fifty-four of these patients had hepatitis testing updated after their 19th year of transplantation. Fifteen patients had evidence of ongoing viral infection: persistent hepatitis B surface antigen in three (6%), HCV antibody (enzyme-linked immunosorbent assay II supplemented by recombinant immunoblot assay) in 11 (20%), and both viruses in one (2%). Of the 10 surviving patients, 8 were tested further for viral replication. HCV RNA (polymerase chain reaction; Amplicore) was positive in 6/7 (86%), and HBV DNA (hybridization) was positive in 1/2 (50%). An elevated alanine aminotransferase (>35 U/L) was present in all hepatitis patients, alpha-fetoprotein >10 ng/ml in 2/8 (25%), and cryoglobulins >50 microg/ml in 3/6 (50%) infected with HCV. No hepatocellular carcinoma was detected by hepatic ultrasound. In patients with chronic viral hepatitis, probable cirrhosis developed in 20% (3/15) compared to one patient in the group without hepatitis, but there was no mortality from liver failure in either group. Diabetes mellitus was significantly more common in those with than without hepatitis (11/15 vs. 10/39; P=0.002), but severe infection was not (9/15 vs. 15/39). Five hepatitis patients (33%) have died of non-hepatic causes (one from meningitis, one from unknown cause, and three from coronary heart disease [CHD] vs. only two individuals without hepatitis [5%]; P= 0.014). Although the more frequent occurrence of CHD among those with hepatitis was not significant (7/15 vs. 8/39; P=0.09), CHD as a cause of death in those with HCV was significantly increased (P=0.03). CONCLUSIONS: Twenty-year renal transplant recipients infected with hepatotropic viruses (HBV and HCV) have a high rate of active viral replication (88%), a greater frequency of diabetes (P=0.01), and a higher overall mortality (P=0.014).

The alloimmunized patient: monitoring and therapeutics.

The sensitization of renal transplant patients in the form of antihuman leukocyte antigen antibodies often constitutes significant risk to allograft function. Testing for these antibodies is done before, at the time of, and after renal transplantation. Correct interpretation of the results necessitates an understanding of the principles of the tests and of the clinical factors in the patients, especially those receiving another transplant. Treatment remains difficult, although preliminary trials with intravenous gamma globulin have shown promising results in some patients.

De novo light-chain deposition disease in a cadaver renal allograft.

The deposition of immunoglobulin (Ig) light chains after renal transplantation most commonly occurs as a manifestation of recurrent multiple myeloma or recurrent light chain nephropathy. We report the development of de novo light chain deposition disease (LCDD) in a cadaveric renal transplant recipient 16 years after transplantation with no evidence of prior multiple myeloma or LCDD and no current evidence of myeloma or lymphoproliferative malignancy.

The fate of renal allografts functioning for a minimum of 20 years (level 5A)--indefinite success or beginning of the end? A proposed classification of long-term allograft survivals.

Fifty-five renal allografts (44 from living-related and 11 from cadaver donors) that have functioned for at least 20 years (mean 22.9 +/- 2.3, range 20.1 to 30.7 years) were evaluated in three groups based on renal function: group I (n = 26), with a GFR of > or = 60 ml/min/1.73 m2 or serum creatinine < or = 1.4 mg/dl and no proteinuria; group II (n = 9), with a GFR of > or = 60 ml/min/1.73 m2 or serum creatinine < or = 1.4 mg/dl but > 150 mg proteinuria/24 hr; and group III (n = 20), with a GFR < 60 ml/min/1.73 m2 and/or serum creatinine > 1.4 mg/dL with or without proteinuria. Allograft factors, including acute rejection (AR) in 62% (34/55) and delayed function (DF) in 55% (6/11) of the cadaver grafts, did not preclude 20-year success and the prospect of continued survival since they were not significantly more frequent in group I, II, or III. However, AR was confined to a limited period within the first three months posttransplant in 18/18 recipients in groups I and II but only in 7/16 of group III (P = 0.0002). In groups I and II AR was treated with IVMP in 14/18 cases and only 6/16 in group III (P = 0.035). Donor age < or = 50 years and recipient age < or = 40 years each occurred in 87% (48/55) of these transplants. One- or two-HLA haplotype matching was present in 98% (43/44) of living related transplants. Major risks to the recipient were coronary artery disease (11 cases and 3 deaths), malignancy (18 cases and 1 death), and severe infection and hepatitis (35 cases and 3 deaths, 2 of whom also had coronary artery disease). Hypertension occurred in 25 recipients and diabetes mellitus in 12. Potential open-end success was compromised by renal dysfunction in groups II and III, but appeared possible in 12 of the 26 patients in group I. There is no apparent "safe-haven" point of time for immunosuppressed renal allograft recipients, who remain at increased risk for eventual renal allograft dysfunction, as well as cardiovascular, neoplastic, infectious, and metabolic diseases. In order to clarify and standardize the words "long-term," a simple classification of long-term allograft survivals is proposed.

Changing demographics in renal transplant recipients: the 30 year Cleveland Clinic experience.

While it does appear that the most recent era of transplantation has not resulted in significant improvement in long-term allograft function, this appears to be due, at least in part, to the transplantation of increasing numbers of high-risk patients. It is noted that the improved results accomplished over prior eras of transplantation have been maintained despite the inclusion of these high-risk patients. Patients currently undergoing transplantation are more likely to be older, diabetic, obese or African American. All of these subgroups have poorer patient survival in the most recent transplant era and thus, death with a functioning graft has become a significant contributor to graft loss. Recipients were more likely to receive kidneys from cadaveric donors in the most recent era and within the live-donor groups, sibling donation has decreased. Hopefully, the recent trend of increased live-donor transplants (especially living, unrelated transplants) will continue. Cadaveric recipients were at higher risk for posttransplant ATN which, for the first time in the current era, had a significant adverse impact on graft survival. Long-term survival appeared to be associated with particular characteristics (optimal age at transplantation, optimal donor age, live donor, etc.), and can be achieved despite known risk factors, such as rejection or delayed graft function.

Allocation of cadaver kidneys: new pressures, new solutions.

Equitable allocation of human cadaver kidneys is complex and challenging, both from the ethical and scientific points of view. It is based on the principles of distributive justice and medical utility. However, the optimal application of ethical principles will require further resolution of medical issues that currently focus on the number of transplants for a single patient, six antigen matches, lesser degrees of HLA matching, marginal recipients, various positive cross-match situations, and cold ischemia time. New HLA matching techniques and enhanced computer organ allocation systems have the potential to surmount racial differences and increase significantly the number of compatible renal allografts.

Coronary artery disease in renal transplant recipients.

BACKGROUND: Coronary artery disease is a major cause of death in transplant recipients. PURPOSE: To review current approaches for the detection, evaluation, and treatment of coronary artery disease in transplant recipients. SUMMARY: Renal transplantation promotes the development of coronary artery disease primarily because immunosuppressant medications accentuate known coronary risk factors such as hypertension, hypercholesterolemia, and hyperglycemia that accelerate the progression of coronary artery disease existing before transplantation. Physicians can monitor a patient's risk status by regular inquiries for symptoms and by simple clinical tools such as the Framingham Study Coronary Heart Disease Risk Prediction Chart in asymptomatic patients. Patients found to be at high risk for coronary artery disease can then undergo dobutamine echocardiography or other noninvasive tests, and patients with positive studies can subsequently undergo angiography. The cost-effectiveness of such an approach is presented. In recent studies at our institution, patients with coronary artery disease had decreased numbers of CD2+ and CD3+ circulating lymphocytes. In addition, in immunosuppressed transplant recipients with coronary artery disease, there was a decrease in CD8+ lymphocytes, whereas in nonimmunosuppressed, nontransplant patients there was a decrease in CD4+ lymphocytes. CONCLUSIONS: A systematic approach to screening patients for coronary artery disease before transplantation can identify those at highest risk and potentially save money and lives. Possible new avenues of research may focus on the role of the lymphocytes in coronary atherosclerosis.