Bryan D. Myers

Cyclosporine-Associated Chronic Nephropathy

We evaluated glomerular filtration in 17 recipients of heart transplants who were treated for 12 months or longer with cyclosporine (cyclosporin A). The control group consisted of 15 heart-transplant recipients who were treated with azathioprine and who had also survived for at least 12 months. Despite an equivalent cardiac output, the glomerular filtration rate was depressed (51 +/- 4 vs. 93 +/- 3 ml per minute, P less than 0.005) in transplant recipients treated with cyclosporine. Cyclosporine treatment was also associated with reduced renal plasma flow (320 +/- 21 vs. 480 +/- 30 ml per minute, P less than 0.001). A trend toward restricted transglomerular transport of neutral dextrans (radii, 2.4 to 5.8 nm) in cyclosporine-treated recipients suggested an intrinsic loss of ultrafiltration capacity by glomerular capillaries rather than a hemodynamic basis for the reduced glomerular filtration rate. Histopathologic examination of the kidneys of five cyclosporine-treated patients with glomerular hypofiltration revealed a variable degree of tubulointerstitial injury accompanied by focal glomerular sclerosis. Among the 32 heart-transplant recipients treated for more than 12 months with cyclosporine at our center, end-stage renal failure developed in 2. We conclude that long-term cyclosporine therapy may lead to irreversible and potentially progressive nephropathy. We recommend that cyclosporine be used with restraint and caution until ways are found to mitigate its nephrotoxicity.

Podocyte loss and progressive glomerular injury in type II diabetes.

Kidney biopsies from Pima Indians with type II diabetes were analyzed. Subjects were classified clinically as having early diabetes (n = 10), microalbuminuria (n = 17), normoalbuminuria, despite a duration of diabetes equal to that of the subjects with microalbuminuria (n = 12), or clinical nephropathy (n = 12). Subjects with microalbuminuria exhibited moderate increases in glomerular and mesangial volume when compared with those with early diabetes, but could not be distinguished from subjects who remained normoalbuminuric after an equal duration of diabetes. Subjects with clinical nephropathy exhibited global glomerular sclerosis and more prominent structural abnormalities in nonsclerosed glomeruli. Marked mesangial expansion was accompanied by a further increase in total glomerular volume. Glomerular capillary surface area remained stable, but the glomerular basement membrane thickness was increased and podocyte foot processes were broadened. Broadening of podocyte foot processes was associated with a reduction in the number of podocytes per glomerulus and an increase in the surface area covered by remaining podocytes. These findings suggest that podocyte loss contributes to the progression of diabetic nephropathy.

Development and Progression of Renal Disease in Pima Indians with Non-Insulin-Dependent Diabetes Mellitus

BACKGROUND Non-insulin-dependent diabetes mellitus (NIDDM) is a major cause of end-stage renal disease. However, the course and determinants of renal failure in this type of diabetes have not been clearly defined. METHODS We studied glomerular function at intervals of 6 to 12 months for 4 years in 194 Pima Indians selected to represent different stages in the development and progression of diabetic renal disease. Initially, 31 subjects had normal glucose tolerance, 29 had impaired glucose tolerance, 30 had newly diagnosed diabetes, and 104 had had diabetes for five years or more; of these 104, 20 had normal albumin excretion, 50 had microalbuminuria, and 34 had macroalbuminuria. The glomerular filtration rate, renal plasma flow, urinary albumin excretion, and blood pressure were measured at each examination. RESULTS Initially, the mean (+/-SE) glomerular filtration rate was 143+/-7 ml per minute in subjects with newly diagnosed diabetes, 155+/-7 ml per minute in those with microalbuminuria, and 124+/-7 ml per minute in those with macroalbuminuria; these values were 16 percent, 26 percent, and 1 percent higher, respectively, than in the subjects with normal glucose tolerance (123+/-4 ml per minute). During four years of follow-up, the glomerular filtration rate increased by 18 percent in the subjects who initially had newly diagnosed diabetes (P=0.008); the rate declined by 3 percent in those with microalbuminuria at base line (P=0.29) and by 35 percent in those with macroalbuminuria (P<0.001). Higher base-line blood pressure predicted increasing urinary albumin excretion (P=0.006), and higher base-line urinary albumin excretion predicted a decline in the glomerular filtration rate (P<0.001). The initial glomerular filtration rate did not predict worsening albuminuria. CONCLUSIONS The glomerular filtration rate is elevated at the onset of NIDDM and remains so while normal albumin excretion or microalbuminuria persists. It declines progressively after the development of macroalbuminuria.

Detection of Renal Function Decline in Patients with Diabetes and Normal or Elevated GFR by Serial Measurements of Serum Cystatin C Concentration: Results of a 4-Year Follow-Up Study

Research on early renal function decline in diabetes is hampered by lack of simple tools for detecting trends (particularly systematic decreases) in renal function over time when GFR is normal or elevated. This study sought to assess how well serum cystatin C meets that need. Thirty participants with type 2 diabetes in the Diabetic Renal Disease Study met these three eligibility criteria: GFR >20 ml/min per 1.73 m2 at baseline (based on cold iothalamate clearance), 4 yr of follow-up, and yearly measurements of iothalamate clearance and serum cystatin C. With the use of linear regression, each individuals trend in renal function over time, expressed as annual percentage change in iothalamate clearance, was determined. Serum cystatin C in mg/L was transformed to its reciprocal (100/cystatin C), and linear regression was used to determine each individuals trend over time, expressed as annual percentage change. In paired comparisons of 100/cystatin C with iothalamate clearance at each examination, the two measures were numerically similar. More important, the trends in 100/cystatin C and iothalamate clearance were strongly correlated (Spearman r = 0.77). All 20 participants with negative trends in iothalamate clearance (declining renal function) also had negative trends for 100/cystatin C. Results were discordant for only three participants. In contrast, the trends for three commonly used creatinine-based estimates of GFR compared poorly with trends in iothalamate clearance (Spearman r < 0.35). Serial measures of serum cystatin C accurately detect trends in renal function in patients with normal or elevated GFR and provide means for studying early renal function decline in diabetes.

A Transcriptional Profile of Aging in the Human Kidney

In this study, we found 985 genes that change expression in the cortex and the medulla of the kidney with age. Some of the genes whose transcripts increase in abundance with age are known to be specifically expressed in immune cells, suggesting that immune surveillance or inflammation increases with age. The age-regulated genes show a similar aging profile in the cortex and the medulla, suggesting a common underlying mechanism for aging. Expression profiles of these age-regulated genes mark not only age, but also the relative health and physiology of the kidney in older individuals. Finally, the set of aging-regulated kidney genes suggests specific mechanisms and pathways that may play a role in kidney degeneration with age.

Effects of Converting-Enzyme Inhibition on Barrier Function in Diabetic Glomerulopathy

Differential solute clearances were used to examine the effects of a 90-day course of enalapril on glomerular barrier function in 16 proteinuric patients with diabetic glomerulopathy. By day 90, plasma renin and prorenin became elevated, and arterial pressure declined. Transglomerular passage of dextrans of broad size distribution (radii 28–60 Å) was lowered significantly. In a subset of 8 patients, withdrawal of enalapril was followed after an additional 30 days by a return of renin levels and arterial pressure to pretreatment levels. The dextran-sieving profile also returned to baseline, becoming uniformly elevated above treated day-90 levels. A theoretical analysis of the serial dextran-sieving profiles indicated that enalapril shifted glomerular pore size distribution to smaller size. These changes in barrier size selectivity were associated with a reduction in fractional albumin and IgG clearances during enalapril therapy and a subsequent rise in these quantities after its withdrawal; urinary protein excretion rate tended to vary in parallel. We conclude that inhibition of converting enzyme in humans with established diabetic glomerulopathy diminishes glomerular permeability to proteins by enhancing barrier size selectivity. Because neither enalapril therapy nor its withdrawal influenced the glomerular filtration or renal plasma flow rates significantly, we propose that the primary action of enalapril may be to modulate the intrinsic membrane properties of the glomerular barrier.

Chronic injury of human renal microvessels with low-dose cyclosporine therapy

Physiologic and morphologic techniques were used to study kidneys of cardiac transplant recipients treated with either low-dose (low-CsA) or high-dose (high-CsA) cyclosporine. After 12 months both low-CsA (4.6 +/- 0.4) and high-CsA (6.3 +/- 0.3 mg/Kg/24 hr, p less than 0.01) were associated with azotemia and hypertension; GFR with each regimen was depressed below values in a third group treated without CsA (no-CsA) by 40-47%, while corresponding renal vascular resistance was elevated greater than 2-fold (P less than 0.01). Morphologic changes in both CsA groups included an obliterative arteriolopathy with downstream collapse or sclerosis of glomeruli. Determination of renal arcuate vein occlusion pressure revealed an increasing renal artery-to-peritubular capillary pressure gradient between 1 and 12 months of CsA therapy. Fractional clearances of dextrans of graded size were elevated at each time compared with the no-CsA group. Analysis of dextran transport with an isoporous membrane model indicates that transglomerular hydraulic pressure difference (delta P) approximated 39 with no-CsA, but was reduced with low-CsA therapy to about 30 at 1 month, and about 34 mmHg after 12 months. We conclude that chronic CsA therapy induces constriction and eventual occlusion of afferent arterioles, causing downstream glomerular damage that is irreversible. Low versus high dosage of CsA confers only marginal protection against this serious microvascular injury.

Elevated Levels of Tumor Necrosis Factor-α in the Nephrotic Syndrome in Humans

To investigate the possible role of cytokines in the mediation of glomerular injury in the nephrotic syndrome, the levels of interleukin (IL)-1β, IL-2, interferon (IFN)-α, IFN-γ, and tumor necrosis factor-α (TNF-α) were measured in patients with primary nephrotic syndrome. These patients had minimal change nephropathy (MCN), focal and segmental glomerulosclerosis (FSGS), or membranous nephropathy (MN) on biopsy. Cytokine levels were assessed by immunoradiometric assays, and specimens consisted of plasma, urine, and the culture supernate of mitogen-stimulated peripheral blood mononuclear cells (PBMC). Only TNF-α was found to be significantly elevated, in the plasma and urine of patients with FSGS and MN, above that found in healthy control subjects and patients with MCN. The elevation of TNF-a could not be shown to correlate with the length or severity of the nephrotic syndrome or with loss of body mass. IL-1β, IL-2, IFN-α, and IFN-γ levels were not elevated. In culture, mitogen-stimulated PBMC from all three groups of nephrotic subjects released an excess of TNF-α compared with controls, a response not consistently observed for the other cytokines measured. The findings of this survey of cytokine levels in nephrotic patients support the possibility that TNF-α may play a pathogenic role in the induction or maintenance of glomerular barrier dysfunction in humans.

Creatinine: An inadequate filtration marker in glomerular diseases☆

Abstract The exaggerated clearance (C) of creatinine relative to inulin in patients with renal disease has been attributed to (1) increased tubular creatinine secretion (TS creatinine ) and (2) reduced inulin filtration due to restricted transglomerular inulin transport. In an attempt to gain further insight into the disparate clearances of these commonly employed markers of glomerular filtration, we performed simultaneous clearance studies of creatinine (Einstein-Stokes radius (ESR) = 3 A, inulin ESR=14 A and dextran fractions with ESR=16 − 24 A) in seven normal subjects, 10 patients with cardiac failure and 38 subjects with the nephrotic syndrome. Notwithstanding equivalent depression of mean C inulin to 47 ± 6 and 42 ± 5 ml/min/1.73 m 2 in cardiac and nephrotic subjects, respectively, C creatinine : C inulin was more increased in the latter (1.70 ± 0.11 versus 1.22 ± 0.14, p dextran : C inulin was not significantly different from unity in all three experimental groups. This suggests that uncharged polysaccharides with ESR creatinine , thus accounting for the increase of C creatinine above C inulin in patients with the nephrotic syndrome.

Limitations of Creatinine in Quantifying the Severity of Cyclosporine-Induced Chronic Nephropathy

The glomerular filtration rate (GFR), as measured by the clearance of inulin, was depressed severely in 34 heart transplant recipients receiving cyclosporine (CsA) for 12 months or longer. The clearance of 99mTc-DTPA, a filtration marker similar in size to creatinine, was identical to that of the larger inulin molecule. In contrast, the clearance of creatinine was enhanced (P less than .01) such that its fractional clearance (relative to inulin) averaged 1.51 +/- 0.05. Moreover, there was an inverse relationship between fractional creatinine clearance (r = 0.36, P less than .01) and absolute inulin clearance. We conclude that in CsA-induced chronic nephropathy 99mDTPA and inulin are unrestricted by the glomerular capillary wall and behave as true filtration markers, creatinine is progressively hypersecreted by renal tubules as the nephropathy worsens, and the ensuing enhancement of creatinine clearance over GFR blunts the expected rise in serum creatinine levels as GFR falls. As a result, serum creatinine in chronic CsA-induced glomerulopathy exceeds 2 mg/dL consistently, only after true GFR has become depressed below normal values by two thirds or more.