Paul E. Klotman

Prospective analysis of strategies for diagnosing renovascular hypertension.

Renovascular hypertension is a potentially curable form of high blood pressure. However, it is unclear how best to select patients who are likely to have renovascular hypertension, what diagnostic strategy to use in these selected patients, and how to predict the hemodynamic significance of a renal artery stenosis. We determined the prevalence of renovascular hypertension in adults who exhibited suggestive clinical features. In these clinically selected patients, we then determined the test characteristics of various diagnostic and potential screening tests. Renovascular hypertension was diagnosed if correction of renal artery stenosis resulted in decreased blood pressure. Of the 66 hypertensive adults evaluated, 11 (16.7%) had renovascular hypertension. Captopril-stimulated peripheral renln activity detected renovascular hypertension with 73% sensitivity, 72% specificity, 38% positive predictive value, and 92% negative predictive value. Less optimal combinations of sensitivity and specificity were found for differential glomerular filtration rate renography, differential effective renal plasma flow renography, and selective renal vein renin ratios, each performed after a single dose of captopril. Intravenous digital subtraction renal angktgraphy detected all patients with renovascular hypertension and was normal in 71% of patients with essential hypertension. To evaluate potential screening tests for renovascular hypertension, we calculated predictive values applied to a low prevalence population. If the observed sensitivities and specificities apply to a population with 5% prevalence of renovascular hypertension, captopril-stimulated peripheral renin would have a positive predictive value of 12% and a negative predictive value of 98%. In 16 patients with known renal artery stenosis, neither the captopril-stimulated renal vein renin ratio nor captopril-stimulated differential renography accurately predicted blood pressure response to correction of the stenosis. We conclude that clinical criteria can identify a subgroup with 16.7% prevalence of renovascular hypertension. In this high prevalence group, intravenous digital subtraction renal angiography will identify virtually all patients with renovascular hypertension, and a normal study will be sufficient to exclude renovascular hypertension. In unselected hypertensive patients, screening with captopril-stimulated peripheral renin activity may be the most useful and efficient procedure for identification of patients with renovascular hypertension. Functional tests do not accurately predict the hemodynamic significance of a renal artery stenosis.

Functional role of thromboxane production by acutely rejecting renal allografts in rats.

We investigated the role of thromboxane in mediating the reduction in renal function and renal blood flow characteristic of acute renal allograft rejection. We transplanted kidneys from Lewis rats to Brown-Norway recipients. By the third day after transplantation, histologic changes that were consistent with cellular rejection occurred in the kidney. These changes were associated with a moderate reduction in renal function. By day 6, histologic changes of rejection were advanced and included interstitial and perivascular infiltration by mononuclear cells. The clearances of inulin and para-aminohippuric acid were also markedly reduced. As renal function deteriorated, thromboxane B2 (TXB2) production by ex vivo perfused renal allografts increased progressively from 2 to 6 d after transplantation. However, prostaglandin (PG) E2 and 6-keto PGF1 alpha production remained essentially unchanged. There was a significant inverse correlation between the in vivo clearance of inulin and the log of ex vivo TXB2 production. Infusion of the thromboxane synthetase inhibitor UK-37248-01 into the renal artery of 3-d allografts significantly decreased urinary TXB2 excretion and significantly increased renal blood flow (RBF) and glomerular filtration rate (GFR). Although renal function improved significantly after the acute administration of UK-37248-01, GFR and RBF did not exceed 33 and 58% of native control values, respectively. In other animals, daily treatment with cyclophosphamide improved the clearances of inulin and para-aminohippuric acid and reduced thromboxane production by 6-d renal allografts. These studies demonstrate that histologic evidence of rejection is associated with increased renal thromboxane production. Inhibition of thromboxane synthetase improves renal function in 3-d allografts. Cytotoxic therapy improves renal function, reduces mononuclear cell infiltration, and decreases allograft thromboxane production. Thus, the potent vasoconstrictor thromboxane A2 may play a role in the impairment of renal function and renal blood flow during acute allograft rejection.

Water deprivation stimulates transforming growth factor-beta 2 accumulation in the juxtaglomerular apparatus of mouse kidney.

Transforming growth factor-beta (TGF-beta) modulates the growth and differentiation of many cells and often functions in an autocrine or paracrine fashion. The myoepithelial cells of the renal juxtaglomerular apparatus (JGA) synthesize and secrete renin. Under conditions which chronically stimulate renin production, the JGA undergoes hypertrophy and hyperplasia. The molecular factors responsible for these changes in the JGA have not been identified. In the present study, plasma renin activity was stimulated in the mouse by water deprivation. Using immunoperoxidase staining with specific antibodies against TGF-beta 1, beta 2, and beta 3, we found increased TGF-beta 2 accumulation in the JGA and interlobular arteries. Immunostaining with renin antiserum demonstrated colocalization of TGF-beta 2 and renin. TGF-beta 1 and beta 3 expression was not different between control and water-deprived mice. Our results suggest that in the setting of water deprivation, TGF-beta 2 is localized in a manner which would allow it to act either as a growth factor for or as a phenotypic modulator of the JGA and renal arterioles.

Thromboxane receptor blockade improves cyclosporine nephrotoxicity in rats

Cyclosporine A (CyA) nephrotoxicity is associated with impaired renal hemodynamic function and increased production of the vasoconstrictor eicosanoid thromboxane A2 (TxA2). In CyA toxic rats, renal dysfunction can be partially reversed by inhibitors of thromboxane synthase. However, interpretation of these results is complicated since inhibition of thromboxane synthase may cause accumulation of prostaglandin endoperoxides that can act as partial agonists at the TxA2 receptor and may blunt the efficacy of treatment. Furthermore, these endoperoxides may be used as substrate for production of vasodilator prostaglandins causing beneficial effects on hemodynamics which are independent of thromboxane inhibition. To more specifically examine the role of TxA2 in CyA toxicity, we investigated the effects of the thromboxane receptor antagonist GR32191 on renal hemodynamics in a rat model of CyA nephrotoxicity. In this model, administration of CyA resulted in a significant decrease in glomerular filtration rate (GFR) (2.85 +/- 0.26 [CyA] vs 6.82 +/- 0.96 ml/min/kg [vehicle]; p less than 0.0005) and renal blood flow (RBF) (21.65 +/- 2.31 [CyA] vs 31.87 +/- 3.60 ml/min/kg [vehicle]; p less than 0.025). Renal vascular resistance (RVR) was significantly higher in rats given CyA compared to animals treated with CyA vehicle (5.32 +/- 0.55 [CyA] vs. 3.54 +/- 0.24 mm Hg/min/ml/kg [vehicle]; p less than 0.05). These renal hemodynamic alterations were associated with a significant increase in urinary excretion of unmetabolized, native thromboxane B2 (TxB2) (103 +/- 18 [CyA] vs 60 +/- 16 pg/hour [vehicle]; p less than 0.05). Only minimal histomorphologic changes were apparent by light microscopic examination of kidneys from both CyA and vehicle treated animals. However, with immunoperoxidase staining, a significantly greater number of cells expressing the rat common leukocyte antigen was found in the renal interstitium of rats given CyA. There was no detectable increase in monocytes/macrophages in the kidneys of CyA toxic animals. In rats treated with CyA, intraarterial infusion of GR32191 at maximally tolerated doses significantly increased GFR and RBF, and decreased RVR. Although both RBF and RVR were restored to levels not different from controls, GFR remained significantly reduced following administration of GR32191. These data suggest that the potent vasoconstrictor TxA2 plays an important role in mediating renal dysfunction in CyA nephrotoxicity. However, other factors may be important in producing nephrotoxicity associated with CyA.

Similar prevalence of renovascular hypertension in selected blacks and whites.

Renovascular hypertension is a potentially curable form of high blood pressure that is thought to be extremely rare among blacks. We demonstrate, however, that in a clinically selected population, the prevalence of renovascular hypertension is similar in blacks and whites. We prospectively evaluated 167 hypertensive subjects who had one or more clinical features known to be associated with renovascular hypertension. All subjects had captopril-stimulated peripheral renin measurements and conventional renal arteriography. All significant renal artery stenoses (greater than 50% luminal narrowing) were treated with percutaneous transluminal angioplasty or surgery. Renovascular hypertension was diagnosed if there was a blood pressure response to interventional therapy, according to the criteria established by the Cooperative Study of Renovascular Hypertension. Of the total group evaluated, 24% (39 of 167) had renal artery stenosis and 14% (23 of 167) had renovascular hypertension. Renal artery stenosis or occlusion was found in 27% (26 of 97) of whites and 19% (13 of 67) of blacks (p=027). Renovascular hypertension was diagnosed in 18% (17 of 97) of whites and 9% (6 of 67) of blacks evaluated (p=0.25). Renovascular hypertension was associated with severe or refractory hypertension and with smoking, but there were no racial differences in these associations. Blacks with renovascular hypertension tended to have low captopril-stimulated peripheral renin activity. We conclude that blacks with clinical features suggestive of renovascular hypertension should be evaluated with angiography. Captopril-stimulated plasma renin may not be useful in detecting blacks with renovascular hypertension, but this and other potential screening tests require further evaluation.

Molecular therapy for renal diseases

The introduction of molecular therapy through the delivery of nucleic acids either as oligonucleotides or genetic constructs holds enormous promise for the treatment of renal disease. Significant barriers remain, however, before successful organ-specific molecular therapy can be applied to the kidney. These include the development of methods to target the kidney selectively, the definition of vectors that transduce renal tissue, the identification of appropriate molecular targets, the development of constructs that are regulated and expressed for long periods of time, the demonstration of efficacy in vivo, and the demonstration of safety in humans. As the genetic and pathophysiologic basis of renal disease is clarified, obvious targets for therapy will be defined, for example, polycystin in polycystic kidney disease, human immunodeficiency virus (HIV) type 1 in HIV-associated nephropathy, alpha-galactosidase A in Fabrys disease, insulin in diabetic nephropathy, and the minor collagen IV chains in Alports syndrome. In addition, several potential mediators of progressive renal disease may be amenable to molecular therapeutic strategies, such as interleukin-6, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta(TGF-beta). To test the in vivo efficacy of molecular therapy, appropriate animal models for these disease states must be developed, an area that has received too little attention. For the successful delivery of genetic constructs to the kidney, both viral and nonviral vector systems will be required. The kidney has a major advantage over other solid organs since it is accessible by many routes, including intrarenal artery infusion, retrograde delivery through the uroexcretory pathways, and ex vivo during transplantation. To further restrict expression to the kidney, tropic vectors and tissue-specific promoters also must be developed. For the purpose of inhibition of endogenous or exogenous genes, current therapeutic modalities include the delivery of antisense oligodeoxynucleotides or ribozymes. For these approaches to succeed, we must gain a much better understanding of the nature of their transport into the kidney, requirements for specificity, and in vivo mechanisms of action. The danger of a rush to clinical application is that superficial approaches to these issues will likely fail and enthusiasm will be lost for an area that should be one of the most exciting developments in therapeutics in the next decade.

Clinical characteristics useful in screening for renovascular disease

In an effort to detect renovascular hypertension, clinical characteristics are used to select patients likely to have renal artery stenosis. We prospectively evaluated the ability of commonly used clinical features to predict the presence of renal artery stenosis in 100 hypertensive adults. All subjects had conventional renal arteriography. Renal artery stenosis was diagnosed if there was 50% or more stenosis of a main renal artery. Eighteen of the 100 had renal artery stenosis. The presence of a bruit was strongly associated with renal artery stenosis (P < .0005). In patients without a bruit, only refractory hypertension was associated with the presence of renal artery stenosis (P = .051). These data suggest that a bruit and refractory hypertension are associated with renal artery stenosis, but that other clinical features investigated may not be and that other means of screening for renovascular disease are needed.

Renovascular Hypertension in Blacks

To define the clinical characteristics of renovascular hypertension (RVH) and determine the clinical usefulness of captopril stimulated peripheral renin and postcaptopril renography in blacks at risk for RVH, 79 clinically selected hypertensive blacks were evaluated. Unstimulated (U-PRA), captopril stimulated (S-PRA) peripheral renin, and postcaptopril renography (PC-RENO) were obtained. All subjects underwent conventional renal arteriography. Renal artery stenosis (RAS) was present in 14 of 79 (18%) patients. Renovascular hypertension (RVH) was found in 7 of 79 (9%) patients. S-PRA had a sensitivity and specificity of 38% and 86% respectively to detect RAS; and a sensitivity and a specificity of 17% and 85% respectively to detect RVH. PC-RENO had a sensitivity and a specificity of 64% and 58% respectively to detect RAS; and a sensitivity and a specificity of 67% and 58% respectively to detect RVH. This study suggests that RAS occurs in 18% of clinically selected hypertensive blacks. RVH was present in 9% of this population. Captopril stimulated peripheral renin and postcaptopril renography are not useful as screening tools for the diagnosis of renovascular disease in blacks. Blacks at high risk should be evaluated with angiography.

Comparison of intravenous digital subtraction angiography and conventional arteriography in defining renal anatomy.

Intravenous digital subtraction renal angiography (IV-DSRA) is frequently used in the preoperative evaluation of living-related (LR) kidney donors. However, the true accuracy of IV-DSRA in the donor population is difficult to assess since abnormalities of the kidney and its circulation are uncommon in this group. Therefore, we evaluated IV-DSRA in a group of patients more likely to have anomalies and abnormalities that would affect LR donor selection, donor nephrectomy, and subsequent transplantation. Hypertensive adults being evaluated for renovascular hypertension had IV-DSRA and conventional renal arteriograms, which were interpreted independently. We determined the accuracy of IV-DSRA, compared with conventional arteriography, in detecting multiple renal arteries, renal artery stenosis, fibromuscular dysplasia, and abnormal renal parenchyma. Technically unsatisfactory studies were excluded from analysis. Of 59 patients evaluated, 37 had abnormalities or anomalies. IV-DSRA failed to detect 28 of 50 findings in these 37 patients. In 21 patients with multiple renal arteries, IV-DSRA underestimated the number of main renal arteries in 8. Significant renal artery stenosis, present in 16 patients, was undetected by IV-DSRA in 3 of these patients. Mild fibromuscular dysplasia was not detected by IV-DSRA in any of the 5 patients with this condition, and abnormalities of renal parenchyma were not detected in 6 of the 8 patients with scarred or cystic kidneys. When compared with conventional renal arteriography in a hypertensive population, the IV-DSRA does not accurately detect abnormalities of the kidney and its circulation. If these data are confirmed in nonhypertensive subjects, preoperative evaluation of LR kidney donors using IV-DSRA alone may fail to detect potentially important anatomic abnormalities.Intavenous digital subtraction renal angiography (IV-DSRA) is frequently used in the preooperative evaluation of living-related (LR) kindney donors. However, the true accuracy of IV-DSRA in th donor population is difficult to assess since abnormalities of the kidney and its circulation are uncomon in this group. Therefore, we evaluated IV-DSRA in a group of patients more likely to have anomalies and abnormalities that would affect LR donor selction, donor nephrectomy, and subsequent transplantation. Hypertensive adults being evaluated for renovascular hypertension had IV-DSRA and conventional renal arteriograms, which were interpreted indepenmdently. We determinded the accuracy of IV-DSRA, compared with conventional arteriography, in detecting multiple renal arteries,l renal artery stenosis, fibromuscular dysplasia, and abnormal renal parentchyma. Technically unsatisfactory studies were excluded from analysis. Of 59 patients evaluted, 37 had abnormalities or anomalies. IV-DSRA failed to detect 28 of 50 findings in these 37 patients. In 21 patients with multiple renal arteries, IV-DSRA underestimated the number of main renal artery stenosis, present in 16 patients, was undetected by IV-DSRA in 3 of these patients. Mild fibromuscular dysplasia was not detected by IV-DSRA in any of the 5 patients with this condition, and abonormalties of renal parenchyma were not detected in 6 of the 8 patients with scarred or cystic kidneys. When compared with conventional renal arteriography in a hypertensive population, the IV-DSRA does not accurately detect abormalities of the kidney and its circulation. It these data are confirmed in nonhypertensivse subjects, preopertive evaluation of LR kindney donors using IV-DSRA alone may fail to detect potentially important anatomic abormalities.

Chapter 47 – HIV-associated Nephropathy

BACKGROUNDnPatients with HIV-1 infection are at risk for developing renal diseases with diverse etiologies. Acute renal failure occurs in up to 20% of hospitalized patients with HIV infection, and chronic renal disease of diverse etiology has been reported. The single most common cause of chronic renal insufficiency in HIV-1+ patients is HIV-associated nephropathy (HIVAN). Typical morphologic features include enlarged kidneys, microcystic tubule dilatation, tubulointerstitial inflammation, and focal and segmental glomerulosclerosis.nnnMETHODSnThe pathogenesis, epidemiology, and treatment options for HIVAN are discussed. In studying the epidemiology of the disease, we reviewed several renal disease databases, including the United States Renal Data Systems and New York State End Stage Renal Disease Network. We have previously reported our experience with HIVAN at Mount Sinai Medical Center.nnnRESULTSnThe exact cause of the renal disease remains unknown. The importance of a direct effect of HIV-1 viral protein(s) or renal HIV-1 gene expression in disease pathogenesis is supported in the murine model of HIVAN, but definitive proof of renal cell infection in humans is lacking. Further study is required to clarify this issue. We estimate that HIVAN is the fourth leading cause of end-stage renal disease (ESRD) among Blacks between the ages of 20 and 64 years, only slightly behind hypertension, diabetes, and chronic glomerulonephritis. At Mount Sinai Hospital HIVAN accounts for 20% of newly diagnosed ESRD in young black adults. It has become the third leading cause of ESRD in this group, after hypertension and diabetes.nnnCONCLUSIONSnIn seropositive patients with renal disease, renal biopsies should be performed to confirm the diagnosis and determine the true incidence. Special attention should be directed toward understanding the underlying cause(s) of HIVAN. A multicenter trial to explore the potential for antiviral therapy in this disease should be initiated.