Richard G. Appel

The link between hypertension and nephrosclerosis

Nephrosclerosis is literally defined as hardening of the kidneys (Greek derivation: nephros, kidney; sklerosis, hardening). It is the result of scarring or replacement of the normal renal parenchyma by dense collagenous tissue. In practice, nephrosclerosis refers to diseases with predominant pathologic changes occurring in the preglomerular microvasculature and secondarily involving the glomeruli and interstitium. The relationship between mild to moderate hypertension and either nephrosclerosis or end-stage renal disease (ESRD) remains circumstantial, although these syndromes have long been associated in the medical literature. Nephrologists credit hypertension as the etiology of nephrosclerosis in 25% of patients initiating Medicare-supported renal replacement therapy, even though other processes may cause similar renal pathologic findings. Strikingly, serum creatinine values infrequently increase in patients with long-standing mild to moderate hypertension. Patients classified as having hypertensive ESRD typically present with advanced disease, making the processes that initiated the renal disease difficult to detect. Nephrologists are twice as likely to label an African-American patient as having hypertensive nephrosclerosis, compared with a white patient, when presented with identical clinical histories. This review proposes that many patients classified as having hypertensive nephrosclerosis actually have intrinsic renal parenchymal diseases, renal artery stenosis, unrecognized episodes of accelerated hypertension, or a primary renal microvascular disease. The familial clustering of ESRD attributed to hypertension in African-Americans and the identification of genes associated with renal injury in animals support the concept that inherited factors may predispose to renal failure. African-American families often have members with ESRD from disparate etiologies, including hypertensive ESRD. This suggests that common mechanisms, be they inherited or environmental, underlie the development of progressive renal failure in diverse forms of nephropathy. Identification of the mechanisms producing susceptibility to progressive renal disease would support the concept that mild to moderate elevations in blood pressure per se are uncommon causes of nephrosclerosis.

Surgical management of dialysis-dependent ischemic nephropathy

PURPOSE This retrospective review describes surgical management of dialysis-dependent ischemic nephropathy. METHODS From February 1987 through September 1993, 340 patients underwent operative renal artery (RA) reconstruction at our center. A subgroup of 20 patients (6 women; 14 men; mean age 66 years) dependent on hemodialysis immediately before RA repair form the basis of this report. Glomerular filtration rates (EGFR) were estimated from at least three serum creatinine measurements obtained 26 weeks before and after operation. A linear regression model was used to estimate the mean rate of change of EGFR before and after RA repair. Comparative analysis of kidney status and change in EGFR were performed. The influence of function response on follow-up survival was determined by the product-limit method. RESULTS Hemodialysis was discontinued in 16 of 20 patients (80%). For these 16 patients, postoperative EGFR ranged from 9.0 to 56.1 ml/min/1.73 m2 (mean 32.4 ml/min/1.73 m2). Two of 16 patients resumed hemodialysis 4 and 6 months after surgery. Discontinuation of dialysis was more likely after bilateral or complete RA repair (15 of 16 patients) versus unilateral repair (one of four patients; p = 0.01). Permanent discontinuation of dialysis was associated with a rapid preoperative rate of decline in EGFR (mean slope log(e) EGFR: -0.1393 +/- 0.0340 without dialysis; -0.0188 +/- 0.0464 with dialysis; p = 0.04, but NS after controlling for multiple comparisons). Immediate increase in EGFR after operation was inversely correlated with the severity of nephrosclerosis (rank correlation: -0.57; 95% confidence interval [-0.83, -0.10]). Follow-up death was associated with dialysis dependence; two deaths occurred among 14 patients not receiving dialysis, whereas five of six patients dependent on dialysis died (p < 0.01). CONCLUSION Surgical correction of ischemic nephropathy can retrieve renal function in selected patients dependent on dialysis characterized by a rapid decline in preoperative EGFR in combination with global renal ischemia treated by complete or bilateral renal revascularization. After RA repair, discontinuation of dialysis may be associated with improved survival rates when compared with continued dialysis dependence.

Nationwide and Long-Term Survey of Primary Glomerulonephritis in Japan as Observed in 1,850 Biopsied Cases

Primary chronic glomerulonephritis is the most common cause of end-stage renal failure in Japan. The incidence in dialysis patients in Japan is about four times higher than in the United States for reason which are unclear. We conducted a nationwide survey on the natural history and treatment of primary glomerulonephritis under a program project from the Ministry of Health and Welfare of Japan entitled ‘Progressive Chronic Renal Disease’. We analyzed patient characteristics, disease onset, clinical data, and histological findings in 1,850 patients with primary glomerulonephritis from 53 institutions in 1985 who underwent renal biopsy at least 5 years ago, and the follow-up study was carried out 8 years after registration. The incidence of diffuse-mesangial proliferative glomerulonephritis is 41.9%, that of minor glomerular abnormalities 17.5%, and that of focal-mesangial proliferative glomerulonephritis 13.0%. Of 1,045 biopsy specimens that were examined by immunofluorescence microscopy, 47.4% showed IgA nephropathy. Half of all cases with primary chronic glomerulonephritis were asymptomatic and were detected on routine health examination. The survival rates at 20 years from the apparent onset or earliest known renal abnormality are: focal glomerular sclerosis 49%, membranoproliferative glomerulonephritis 58%, diffuse-mesangial proliferative glomerulonephritis 66%, focal-proliferative glomerulonephritis 81%, membranous nephropathy 82%, minor glomerular abnormalities 94%, and IgA nephropathy 61%. In conclusion, a high incidence of IgA nephropathy and a better renal survival of membranous nephropathy are the features of primary chronic glomerulonephritis in Japan. This high incidence of IgA nephropathy together with its poor prognosis is probably the reason for the increased incidence of primary chronic glomerulonephritis in dialysis patients in Japan. In addition, the importance of routine health examination including urinalysis is demonstrated.

Renal duplex sonography after treatment of renovascular disease.

PURPOSE To define the value of renal duplex sonography (RDS) to detect the presence of critical renal artery (RA) stenosis or occlusion after surgical repair or percutaneous transluminal balloon angioplasty (PTRA), we retrospectively reviewed our recent 71-month experience. METHODS From January 1987 through November 1992, 272 patients underwent 279 operative RA repairs and 35 patients underwent PTRA. Three hundred twenty-five RDS examinations were performed in 176 patients after operative intervention or PTRA during the study period. Forty-one of these patients had conventional angiography providing 61 RA for RDS comparison, and these data form the basis of this analysis. Twenty-four women and 17 men (mean age 57 years) underwent 44 operative RA repairs or 17 PTRA for correction of atherosclerotic disease (51 arteries) or fibromuscular dysplasia (10 arteries). Before their renovascular procedure each patient had significant hypertension (mean 193/106 mm Hg). RDS after surgery or PTRA was technically complete for all 61 RA. RESULTS Compared with angiography RDS correctly identified 47 of 48 repairs with less than 60% RA stenosis , 7 of 11 repairs with 60% to 99% stenosis, and 2 renal artery occlusions, providing a 69% sensitivity rate, 98% specificity rate, 90% positive predictive value, and a 92% negative predictive value. These results were adversely affected by branch RA disease, which accounted for three of four false-negative RDS study results. For 50 kidneys undergoing correction of main RA disease, RDS demonstrated an 89% sensitivity rate, 98% specificity rate, and 96% overall accuracy. RDS results were equivalent for both surgical and PTRA treatment. CONCLUSIONS From this experience we conclude that RDS is useful for anatomic evaluation after surgical RA repair or PTRA. A negative RDS result excludes stenosis or occlusion of a main RA reconstruction but does not exclude significant branch level disease.

Genetic Initiation of Hypertensive and Diabetic Nephropathy

The factors initiating the common etiologies of chronic renal failure remain elusive. This article reviews the evidence in support of a generalized genetic susceptibility to human end-stage renal disease, including kidney failure attributed to the systemic diseases of hypertension, diabetes mellitus, and glomerulonephritis. Molecular genetic techniques are powerful tools, assisting in the detection of the initiating factors in many complex diseases. In kidney disease, genetic methodologies complement the available anatomic, epidemiologic, and physiologic analyses. This article provides strategies to allow for the detection of human renal failure susceptibility genes. The identification of human renal failure genes would provide useful markers for disease susceptibility and speed the development of novel therapeutic strategies.

Effect of atrial natriuretic factor on cytosolic free calcium in rat glomerular mesangial cells

Since atrial natriuretic factor (ANF) inhibits angiotensin II (ANGII)‐induced mesangial cell contraction, we studied its effect on cytosolic free calcium in fura‐2‐loaded monolayers. ANF lowered basal calcium from 117 ± 5 to 89 ± 2 nM, and also reduced the ANGII‐induced calcium transient. The absolute level of cytosolic calcium after ANGII was lower in cells preincubated with ANF compared to buffer. In a few cell lines, ANF had no effect on cytosolic calcium, while in all cell lines ANF had inhibited contraction. Thus, while ANF has effects on cytosolic calcium in mesangial cells, the vasorelaxant effects of ANF may require additional physiologic interactions.

Human Immunodeficiency Virus-Associated Nephropathy: Current Concepts

A distinct form of renal disease has been described in patients at various stages of HIV infection that is becoming increasingly important as a cause of morbidity and mortality. Black race and intravenous drug abuse appear to predispose one to its development. The HIV-associated nephropathy is characterized by nephrotic-range proteinuria, rapid progression to end-stage renal disease, a diffuse sclerosing glomerulopathy with significant tubulo interstitial disease seen on light microscopy, and tubuloreticular inclusions seen via electron microscopy. The entity can be separated from heroin-associated nephropathy. The pathogenesis is unclear. Possibilities include direct invasion of the virus, effects of other viruses, genetic factors, immune factors, and multiple growth factors. Not all patients with HIV infection and renal disease have HIV-associated nephropathy. Because of prognostic and therapeutic implications, it is crucial to differentiate these lesions. Some reports suggest a possible beneficial effect of zidovudine therapy, but more study is required. Patient survival is dependent on the stage of HIV infection. Dialysis therapy does not appear to substantially prolong life in most patients with AIDS and irreversible renal failure. Therefore, a number of ethical issues have arisen that deal with medical futility.

IgA Nephropathy and Reiter’s Syndrome

Immunoglobulin A (IgA) nephropathy is the commonest type of primary glomerulonephritis worldwide. It has previously been reported in association with the seronegative spondyloarthropathies (ankylosing spondylitis, Behcet’s syndrome, psoriatic arthritis, Reiter’s syndrome and the postenteritic arthritides). Since this condition was first described in 1968, 5 previous case reports of biopsy-proven IgA nephropathy associated with Reiter’s syndrome have been published in the English-language literature. Here we report 2 more such cases, along with a review of the literature describing the association of IgA nephropathy and a number of other immune-complex-mediated glomerulonephritides with the seronegative spondyloarthropathies.

Papillary collecting tubule synthesis of prostaglandin E2 in Dahl rats.

Isolated kidneys of Dahl salt-sensitive rats (DS) excrete sodium less readily than those of Dahl salt-resistant rats (DR). The collecting tubule is an important source of papillary prostaglandin E2 and is a site of significant sodium reabsorption. We cultured renal papillary collecting tubule cells from 5-week-old, prehypertensive DS and DR on a low salt diet and also after 14 weeks of high salt feeding, and we measured prostaglandin E2 synthetic capacity. Unstimulated renal papillary collecting tubule cells from 5-week-old DS produced 62 +/- 5% less prostaglandin E2 than did comparable cells from DR (p less than 0.001). The cells from DS also synthesized less prostaglandin E2 after stimulation with the calcium ionophore A23187 (67 +/- 6% of control; p less than 0.001) or the addition of exogenous arachidonate (74 +/- 7% of control; p less than 0.01). Urinary prostaglandin E2 excretion was also diminished in the 5-week-old DS compared with their salt-resistant counterparts (18.1 +/- 1.3 vs 23.9 +/- 1.7 ng/24 hr; p less than 0.025). After high salt feeding, the DS became hypertensive but the DR remained normotensive. Renal papillary collecting tubule cells cultured from these DS continued to produce less prostaglandin E2 than those from control rats, both in the basal state (60 +/- 12% of control; p less than 0.09) and after stimulation with ionophore (62 +/- 2% of control; p less than 0.002). In these older animals, the DS continued to underexcrete prostaglandin E2 compared with the DR (29.7 +/- 3.2 vs 42.2 +/- 6.1 ng/24 hr; p less than 0.08). The underproduction of prostaglandin E2 in the papillary collecting tubule of DS may play a role in their inadequate renal natriuretic capacity and contribute to the onset and maintenance of salt-induced hypertension in this strain.

Renovascular hypertension in the elderly: Results of surgical management

This review summarizes our experience with the operative management of renovascular hypertension (RVH) in elderly patients (≥ 60 years of age). From 7/87 through 6/95,230 of 428 adult patients (54%) undergoing operation of renovascular hypertension at our center were in their seventh (153 patients), eighth (70 patients) or ninth (7 patients) decade of life (mean age: 68 years). There were 117 males and 113 females with blood pressures ranging from 280/190 to 178/90 (mean: 202/102 mmHg). One hundred and eighty patients (78%) had renal insufficiency (i.e., serum creatinine ≥ 1.3 mg/dl). One hundred and four patients (45 %) had severe insufficiency (i.e., serum creatinine ≥2.0 mg/dl), with 23 of these patients being dialysis dependent prior to operation. Two hundred and eighteen (95%) had evidence of organ specific atherosclerotic damage as manifested by cardiac disease (93%), cerebrovascular disease (38%) or renal insufficiency (78%). Operative management consisted of a unilateral procedure in 100 patients, bilateral procedures in 130 patients, including 26 nephrectomies. Simultaneous aortic replacement was performed in 95 patients (41%; 59 AAA and 36 occlusive disease). After surgery, there were 13 operative deaths (6%) and 13 renal artery repairs failed (4%). Hypertension was cured (9%) or improved (77%) in 86% of operative survivors. Renal function was improved in 43% and worsened in 15% of patients with nondialysis dependent renal insufficiency. Eighteen of twenty-three patients (78%) who were dialysis dependent before surgery were removed from dialysis following renal revascularization. On follow-up (mean: 29 months), we found that 28 patients died. Multivariate analysis demonstrated that preoperative congestive heart failure (p = 0.007) and increased serum creatinine (p = 0.001) were significant and independent predictors of death on follow-up. Estimated survival was significantly increased among patients with improved renal function after operation compared with patients unimproved. This review emphasizes the complexity of atherosclerosis in the elderly population presenting for operative management of renovascular hypertension. Despite the complexity of disease, our experience suggests that operative management is beneficial and can be accomplished with acceptable, albeit increased, risk in properly selected elderly patients. For elderly patients with renovascular disease in combination with renal insufficiency (i.e., ischemic nephropathy), improved renal function after operation may convey improved survival.