William E. Braun

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.

Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease

BACKGROUND Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin-angiotensin-aldosterone system, and progression of kidney disease. METHODS In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m(2) of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting-enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume. RESULTS The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (-1.17 vs. -0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002). CONCLUSIONS In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686.).

Ineffectiveness of dipyridamole spect thallium imaging as a screening technique for coronary artery disease in patients with end-stage renal failure

The efficacy of dipyridamole single photon emission computed tomography (SPECT) thallium as a screening test for coronary artery disease (CAD), was studied in 45 patients with end-stage renal failure undergoing evaluation for renal transplantation. Coronary arteriography, dipyridamole SPECT thallium imaging and clinical follow-up were performed in all patients. Nineteen patients (42%) had an obstruction of 50% or more in at least one coronary artery. Fourteen patients had a positive thallium scan, but 7 of these were false-positives (sensitivity 37%, specificity 73%). The sensitivity was considerably lower than that quoted for non-ESRF patients in the literature, and significantly lower than a control group of 19 patients without ESRF having comparable severity and distribution of CAD. Five of the 6 patients who died of cardiac causes over a mean follow-up period of 25 months had normal thallium imaging, but all had significant coronary artery disease at cardiac catheterization. Dipyridamole SPECT thallium imaging has not proved a useful screening test for angiographically significant CAD, and does not predict cardiac prognosis in this population.

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 especial 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.

Lymphoceles associated with renal transplantation: Report of 15 cases and review of the literature

Abstract Within a 27 month period (from July 1, 1971 to October 1, 1973), during which 83 renal allotransplantations were performed at the Cleveland Clinic, a lymphocele developed in 15 patients (18.1 per cent). Early clinical symptoms, occurring within 6 weeks after transplantation, were suprapubic or lower abdominal swelling in 14 patients, leg swelling ipsilateral to the allograft in 12, nonpitting edema in the allograft area in 10 and lymph drainage from the wound in 8. An intravenous pyelogram demonstrated a lymphocele in 13 patients from 1 to 34 weeks after transplantation (mean 7.8 weeks), although an earlier suggestion of bladder displacement and deformity was found retrospectively in 5 patients between 1 and 3 weeks after transplantation. Lymphangiograms aided in the diagnosis in nine patients. The major complication of the lymphoceles was obstructive uropathy that developed in nine patients between 2 and 34 weeks after transplantation (mean 10.3 weeks). Lymphoceles mimicked rejection, urine extravasation, pyelonephritis, thrombophlebitis and a seroma, and occurred concurrently with rejection and pyelonephritis. Treatment by external surgical drainage was more effective than aspiration both in resolving the lymphocele and in avoiding infection. Three lymphoceles drained spontaneously 1 to 2 weeks after transplantation, and three are under observation. Chemical and protein analyses were made of the lymphocele fluid obtained from seven patients. Numerous factors may contribute to the formation of a lymphocele by increasing lymph flow. The most prominent factors are the extent of surgical dissection, the occurrence of rejection, and the use of diuretics, large doses of corticosteroids, and anticoagulants. The literature on lymphoceles in renal allograft recipients is reviewed, and pertinent comparisons are made with the more numerous reports of lymphoceles in nontransplant patients.

Donor Kidney Volume and Outcomes Following Live Donor Kidney Transplantation

Pre‐donation kidney volume and function may be crucial factors in determining graft outcomes in kidney transplant recipients. We measured living donor kidney volumes by 3D helical computed tomography scanning and glomerular filtration rate (GFR) by 125I‐iothalamate clearances in 119 donors, and correlated these values with graft function and incidence of acute rejection at 2 years post‐transplantation. Kidney volume strongly correlated with GFR (Pearson r= 0.71, p < 0.001). Body size and male gender were independent correlates of larger kidney volumes, and body size and age were predictors of kidney function. The effects of transplanted kidney volume on graft outcome were studied in 104 donor‐recipient pairs. A transplanted kidney volume greater than 120 cc/1.73 m2 was independently associated with better estimated GFR at 2 years post‐transplant when compared to recipients of lower transplanted kidney volumes (64 ± 19 vs. 48 ± 14 mL/min/1.73 m2, p < 0.001). Moreover, recipients of lower volumes had a higher incidence of acute cellular rejection (16% vs. 3.7%, p = 0.046). In conclusion, kidney volume strongly correlates with function in living kidney donors and is an independent determinant of post‐transplant graft outcome. The findings suggest that (1) transplantation of larger kidneys confers an outcome advantage and (2) larger kidneys should be preferred when selecting from otherwise similar living donors.

The HALT Polycystic Kidney Disease Trials: Design and Implementation

BACKGROUND AND OBJECTIVES Two HALT PKD trials will investigate interventions that potentially slow kidney disease progression in hypertensive autosomal dominant polycystic kidney disease (ADPKD) patients. Studies were designed in early and later stages of ADPKD to assess the impact of intensive blockade of the renin-angiotensin-aldosterone system and level of BP control on progressive renal disease. Design, settings, participants, and measurements: PKD-HALT trials are multicenter, randomized, double-blind, placebo-controlled trials studying 1018 hypertensive ADPKD patients enrolled over 3 yr with 4 to 8 yr of follow-up. In study A, 548 participants, estimated GFR (eGFR) of >60 ml/min per 1.73 m(2) were randomized to one of four arms in a 2-by-2 design: combination angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) therapy versus ACEi monotherapy at two levels of BP control. In study B, 470 participants, eGFR of 25 to 60 ml/min per 1.73 m2 compared ACEi/ARB therapy versus ACEi monotherapy, with BP control of 120 to 130/70 to 80 mmHg. Primary outcomes of studies A and B are MR-based percent change kidney volume and a composite endpoint of time to 50% reduction of baseline estimated eGFR, ESRD, or death, respectively. RESULTS This report describes design issues related to (1) novel endpoints such as kidney volume, (2) home versus office BP measures, and (3) the impact of RAAS inhibition on kidney and patient outcomes, safety, and quality of life. CONCLUSIONS HALT PKD will evaluate potential benefits of rigorous BP control and inhibition of the renin-angiotensin-aldosterone system on kidney disease progression in ADPKD.

Angiotensin Blockade in Late Autosomal Dominant Polycystic Kidney Disease

BACKGROUND Hypertension develops early in patients with autosomal dominant polycystic kidney disease (ADPKD) and is associated with disease progression. The renin-angiotensin-aldosterone system (RAAS) is implicated in the pathogenesis of hypertension in patients with ADPKD. Dual blockade of the RAAS may circumvent compensatory mechanisms that limit the efficacy of monotherapy with an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin II-receptor blocker (ARB). METHODS In this double-blind, placebo-controlled trial, we randomly assigned 486 patients, 18 to 64 years of age, with ADPKD (estimated glomerular filtration rate [GFR], 25 to 60 ml per minute per 1.73 m(2) of body-surface area) to receive an ACE inhibitor (lisinopril) and placebo or lisinopril and an ARB (telmisartan), with the doses adjusted to achieve a blood pressure of 110/70 to 130/80 mm Hg. The composite primary outcome was the time to death, end-stage renal disease, or a 50% reduction from the baseline estimated GFR. Secondary outcomes included the rates of change in urinary aldosterone and albumin excretion, frequency of hospitalizations for any cause and for cardiovascular causes, incidence of pain, frequency of ADPKD-related symptoms, quality of life, and adverse study-medication effects. Patients were followed for 5 to 8 years. RESULTS There was no significant difference between the study groups in the incidence of the composite primary outcome (hazard ratio with lisinopril-telmisartan, 1.08; 95% confidence interval, 0.82 to 1.42). The two treatments controlled blood pressure and lowered urinary aldosterone excretion similarly. The rates of decline in the estimated GFR, urinary albumin excretion, and other secondary outcomes and adverse events, including hyperkalemia and acute kidney injury, were also similar in the two groups. CONCLUSIONS Monotherapy with an ACE inhibitor was associated with blood-pressure control in most patients with ADPKD and stage 3 chronic kidney disease. The addition of an ARB did not alter the decline in the estimated GFR. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study B] ClinicalTrials.gov number, NCT01885559.).

Vascular complications of renal transplantation

From January, 1963, to May, 1979, 600 renal transplants were performed at the Cleveland Clinic. There were 21 vascular complications in this series (3.5%). Arterial complications included renal artery thrombosis in 5 patients, renal artery stenosis in 9 patients, and anastomotic hemorrhage in 2 patients. Venous complications included renal vein thrombosis in 2 patients and hemorrhage in 3 patients. Although vascular complications led directly to graft loss in 10 patients, only 1 resulted in patient death.

Utility of leflunomide in the treatment of complex cytomegalovirus syndromes.

Background. Cytomegalovirus (CMV) viremia that is resistant or refractory to the standard antiviral therapy still constitutes a major threat to high-risk transplant recipients. In addition, multiple CMV recurrences may lead to neutropenia because of repeated courses of therapy with ganciclovir derivatives. Leflunomide, a drug for rheumatoid arthritis, has been reported to have anti-CMV activity. This study reports on its use in 17 transplant recipients with complex CMV syndromes who had failed or were intolerant to other therapies. Methods. Single-center, retrospective study. Clinical data were extracted from the electronic medical record. CMV DNA viral loads were performed by quantitative hybrid capture assay. Results. Leflunomide was initiated after a median of three episodes of CMV viremia, with a mean peak viral load of 245,826 copies/mL. Initial clearance of CMV viremia was observed in 14 of 17 patients (82%), and 9 of 17 (53%) patients achieved a long-term suppression of CMV recurrences. Higher peak viral load and higher viral load at the start of leflunomide therapy were associated with failure to suppress viremia. The duration of leflunomide therapy ranged from 1 to 24 months (median 3.5 months, interquartile range 2.6–7 months), and the mean time to an undetectable CMV-DNA was 1.9 months. Adverse effects included diarrhea (35%), anemia (18%), and increased liver function tests (12%). Conclusions. Leflunomide, alone or in combination, has potential utility in treatment of complex CMV syndromes and in long-term suppression of viremia. The optimal duration of therapy and the balance of risks and benefits are not yet known.