Verapamil improves the outcome after cadaver renal transplantation.

Because of their favorable effects on renal hemodynamics, calcium antagonists may have a major role in the prevention and management of certain types of acute renal dysfunction. In fact, verapamil (VP) was shown to prevent cyclosporin A (CsA)-induced decreases in RBF in mice and in cadaver renal transplant (CRT) recipients. The study presented here of 59 cadaver renal transplant patients evaluates the outcome from perioperative treatment with VP (N = 30) administered intraoperatively into the renal artery (10 mg) followed by oral administration of 120 mg every 8 to 12 h for 14 days versus no drug (N = 29). Early immunosuppression included azathioprine, corticosteroids, and antilymphocyte globulin with subsequent overlapping with CsA on days 5 and 6. Actuarial graft survival at 1 yr was different when the two groups were compared (P less than 0.05). Estimated graft survival at 1 yr for VP patients was 93.3 compared with 72.4% in control patients. The improved graft survival was most striking in repeat transplants with 90% graft survival at 1 yr for VP recipients versus 37.5% for controls. Compared with controls, VP recipients had significantly improved renal parenchymal diastolic blood flow velocities on the first day after surgery (7.8 versus 5.8 cm/s). By day 7, GFR were greater with VP (44 +/- 29 mL/min) versus controls (28 +/- 22 mL/min). Of VP patients, 67% (18 of 24) had GFR greater than 30 mL/min versus 33% (9 of 26) for control patients. Similarly, on the seventh day, 77% (21 of 30) of VP patients had serum creatinines less than 2.0 mg% versus 34% (10 of 29) for controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Reset tubuloglomerular feedback permits and sustains glomerular hyperfunction after extensive renal ablation.

To determine the contribution of the tubuloglomerular feedback (TGF) system to glomerular hyperfunction after extensive loss of renal mass, TGF was assessed in anesthetized Sprague-Dawley rats 7 days after 5/6 reduction of renal mass (2/3 infarction of 1 kidney plus contralateral nephrectomy) or sham surgery. Five-sixths renal ablation significantly increased single-nephron (SN) glomerular filtration rate (GFR) 57%, late proximal tubule fluid flow 58-63%, and maximal proximal tubule stop-flow pressure (PSF) 24%. Despite these increments, 5/6 ablation did not increase TGF activation, as judged by the difference between proximally and distally measured SNGFR values, nor did it affect maximal TGF responses, measured as change in PSF during forward microperfusion of the loop of Henle. However, 5/6 ablation increased the late proximal perfusion rate eliciting half-maximal PSF suppression (V1/2) from 27.3 +/- 1.6 to 45.7 +/- 2.4 nl/min (P less than 0.001), a change closely matching the increment in native late proximal tubule fluid flow from 26.6 +/- 2.2 to 43.8 +/- 2.1 nl/min (P less than 0.001). Unilateral nephrectomy increased V1/2 less dramatically than did 5/6 ablation, thus showing that the effects of renal ablation on TGF are proportional to the degree of ablation. We conclude that extensive renal ablation resets TGF operation in a way that permits and helps sustain glomerular hyperfunction.

Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat.

To examine angiotensin (ANG) concentrations in fluid compartments near known intrarenal ANG receptors, we measured ANG concentrations in glomerular filtrate (GF), star vessel plasma (SVP), and luminal fluid from the early, mid, and late proximal tubule (E, M, and L PT). Samples were collected from euvolemic Munich-Wistar rats by free-flow micropuncture; ANG concentrations were measured by RIA. In one group of rats, concentrations of total immunoreactive ANG (reflecting ANG II and lesser amounts of three fragments) in GF and E, M, and L PT fluid averaged 29-40 nM compared with 32 pM in systemic plasma. In a second group, immunoreactive ANG concentrations in SVP also exceeded systemic levels by a factor of 1,000. In a final group, samples of GF and LPT fluid were purified by HPLC before RIA to measure ANG II and III concentrations specifically: their respective concentrations were 6-8 nM and 14-25 nM. We interpret these results to indicate that substantial amounts of ANG peptides are released into or generated within intrarenal fluid compartments, in which local ANG is likely to effect regulation of renal function independently of systemic ANG.

Acquired immunodeficiency syndrome and the kidney.

Initial autopsy studies concerned primarily with the systemic manifestations of the acquired immunodeficiency syndrome (AIDS) did not indicate that significant renal problems were likely to occur in AIDS patients. However, several recent studies have suggested that important renal and electrolyte disorders develop frequently in at least some groups of AIDS patients. In this report, we review current information concerning such disorders and describe our study of the frequency and types of renal lesions in the first 50 AIDS patients undergoing autopsy at this institution. We conclude that a number of renal lesions and electrolyte abnormalities occur in AIDS patients, although the frequency and nature of these problems vary considerably from center to center. Studies from several centers, including our own, indicate that AIDS patients are particularly likely to develop tubulointerstitial lesions (such as nephrocalcinosis and interstitial nephritis) and electrolyte disorders. Additional studies from specific centers in New York City, Miami, Detroit, and Los Angeles indicate that AIDS patients can also develop glomerular lesions, including a variant of focal and segmental glomerulosclerosis (FSGS) associated with heavy proteinuria and rapidly progressive renal failure. Although FSGS is not commonly observed in all centers, AIDS patients with this lesion appear to have a distinctive combination of clinical and pathological features, suggesting that they have a specific "human immunodeficiency virus (HIV)-associated" nephropathy. Preliminary evidence suggests that this lesion may be related to direct renal HIV infection, although confirmation of this possibility is needed. The approach to the AIDS patient with renal disease should involve correction of reversible disorders and consideration of dialysis as necessary.

Protein intake and cation transport in the loop of Henle.

High-protein intake enhances maximal urinary concentrating ability and suppresses tubuloglomerular feedback activity in a manner that correlates with enhanced salt reabsorption in the loop of Henle. In this article we describe studies designed to localize the site at which protein intake alters loop sodium uptake (JNa) in rats fed diets containing either 6% or 40% protein for approximately 8 to 10 days. In vivo microperfusion demonstrated that luminal bumetanide (10(-5) mol/L) fully reversed the stimulation of JNa by high-protein intake, thus suggesting that high-protein intake stimulates salt transport in the thick ascending limb. In vitro studies supported this possibility, showing that high-protein intake significantly increased sodium-potassium adenosine triphosphatase (NaK ATPase) activity in homogenates of outer renal medulla (68%) and in dissected medullary thick ascending limbs (87%). This effect was partly selective, since high-protein intake did not alter NaK ATPase activity in superficial renal cortex, had a smaller and statistically insignificant effect on NaK ATPase activity in dissected pars rectae, and did not affect magnesium ATPase activity in any tissue. Furthermore, this effect did not appear to require hypertrophy, since high-protein intake for approximately 8 days did not detectably alter the relative amounts of tissue protein and DNA in either medulla or cortex. A last series of studies demonstrated that high-protein intake increased plasma aldosterone levels. We conclude that increased protein intake stimulates salt reabsorption predominantly in the thick ascending limb, an effect that is partly selective; does not appear to require hypertrophy; and may be related to increased plasma aldosterone levels.

Effect of unilateral nephrectomy on three patients with histopathological evidence of diabetic glomerulosclerosis in the resected kidney.

Diabetes mellitus and surgical ablation of renal tissue are two independent influences associated with hyperfiltration and elevated levels of the glomerular transcapillary hydraulic pressure differential (delta P). There is increasing evidence that hyperfiltration with elevated delta P is pathogenic and leads to glomerular damage. The authors questioned whether these two influences (surgical ablation of renal tissue and diabetes mellitus) would act in an additive fashion in human patients to produce an accelerated decline in renal function. Three patients with non-insulin-dependent diabetes mellitus who had undergone a unilateral nephrectomy (for a variety of reasons) were (retrospectively) identified. In each patient, morphologic evidence of diabetic glomerulonephropathy was present in the resected kidney. The charts from these patients were reviewed and post-nephrectomy renal function was estimated over time by plotting reciprocal serum creatine values versus time. Follow-up intervals after nephrectomy varied from 4 to 15 years. The results of our follow-up showed no obvious detrimental effect on renal function (as measured by 1/serum creatinine) attributable to the unilateral nephrectomy. The authors conclude that residual renal function (and ultimate outcome) in patients with non-insulin-dependent diabetes mellitus is highly variable, but does not seem to be adversely affected (at least over the time span of observation in these patients) by unilateral nephrectomy.

Modification of tubuloglomerular feedback signal by dietary protein.

Compared with the effects of a 6% protein diet, feeding rats a 40% protein diet for 10 days increases glomerular filtration rate and decreases the activity of the tubuloglomerular (TG) feedback control system. The decrease in TG feedback activity results from an increase in the threshold at which the loop of Henle flow rate initiates feedback responses. To determine whether this protein-dependent shift in the TG feedback response curve is caused by changes in either the signal or the sensing mechanism in the feedback pathway, we used micropuncture and microperfusion techniques to study the TG feedback system of rats fed high- or low-protein (40 or 6% casein) diets for approximately 7-10 days. Compared with the rats fed the low-protein diet, in the high-protein group distally measured single nephron glomerular filtration rate was 17% higher, and Na and Cl concentrations in early distal tubule fluid were 30-50% lower. Early distal osmolality was not different in the two groups. TG feedback responses assessed by changes in stop-flow pressure during perfusion of the distal nephron with NaCl solutions did not differ between diet groups. We conclude that the sensing mechanism in the TG feedback system is not altered by this manipulation of dietary protein, whereas the signal eliciting the TG feedback response is affected. Because rats fed a high-protein diet have higher rates of Na and Cl absorption between the late proximal and early distal tubules than do rats fed a low-protein diet, early distal Na and Cl concentrations are reduced, and the signal for TG feedback is diminished in rats fed the high-protein diet.

A review of nephrotic syndrome associated with chronic lymphocytic leukemia.

Four patients had the nephrotic syndrome and chronic lymphocytic leukemia (CLL), which may be pathogenetically related. Membranoproliferative glomerulonephritis appears to be the most common glomerular lesion in patients with CLL. Available evidence suggests that nephrotic syndrome associated with CLL is often related to immune-complex disease. It is also possible that disorders of immunoglobulin production and cellular immunity contribute to renal disease in patients with CLL.

Dietary protein suppresses feedback control of glomerular filtration in rats.

We have examined the possibility that changes in glomerular filtration rate (GFR) after changes in dietary protein intake may depend on altered function of the tubuloglomerular (TG) feedback system. We studied male Sprague-Dawley rats after dietary pretreatment for 9.6 +/- 3.6 (SD) d with isocaloric diets containing either 6% or 40% casein. We found that GFR in rats fed the high protein diet was 24-29% higher than in rats fed the low protein diet. Simultaneous measurements of single nephron GFR (SNGFR) in the distal tubule were 6.3 nl/min or 21% higher in the rats fed the high protein diet whereas proximally measured SNGFR was not statistically different in the two groups. The higher distally measured SNGFR of rats receiving the high protein diet was associated with a 4.2 nl/min or 50% smaller suppression of SNGFR by TG feedback (-4.3 vs. -8.5 nl/min, P less than 0.001). Loop perfusion experiments demonstrated that in rats fed the high protein diet the TG feedback mechanism was less sensitive than in rats fed the low protein diet. The TG feedback response in rats fed the low protein diet, as assessed by reductions in stop-flow pressure and SNGFR, was half-maximal at flows of 14-15 nl/min. In contrast, the TG feedback response in rats fed the high protein diet was half-maximal at 22-24 nl/min. Maximal suppression of stop-flow pressure and SNGFR and the slope of the TG feedback response to increasing loop flow rates were not different in the two groups. We conclude that the sensing mechanism of the TG feedback system is rendered less responsive by a high protein intake, and that this change permits GFR to increase.

Virus infections of the respiratory tract cytopathologic and clinical analysis.

Thirty-three cases of respiratory tract virus infections diagnosed cytologically are reviewed. The clinical and demographic data are presented and correlated with an analysis of the cytologic findings. Herpes virus was the most common infection. It occurred in patients with other severe medical problems and had little apparent effect on the clinical outcome of any particular case. Quantitative and qualitative cytologic findings did not correlate with the severity of the herpetic infection. The virus was isolated in culture in only one of 21 cases of Herpes virus infection. Cases in the later part of the study indicate an increasing incidence or recognition of the infection in the respiratory tract. In this series there was a clustering of Herpes virus cases in relation to date of admission and hospitalization in respiratory intensive care. Cytomegalovirus infection was recognized in four cases. This infection occurs in the immune suppressed patient and can be made reliably from cytologic findings. Smears must be screened thoroughly and carefully as the characteristic inclusion is seen in only a rare cell. Bronchial brushing specimens are the most useful. The disease should not be fatal if the level of immune suppression can be manipulated and the patients basic medical problem is not too severe. Cytologic findings contribute little information to tjor medical problems and the adenovirus infection was incidental. Thy cytologic findings in some cases may be non-specific since antibody studies and culteral confirmation are lacking in these cases.