Pathophysiology and management of progressive renal disease.

Recently, the hypothesis that all renal diseases are inherently progressive and self-perpetuating has focused attention on adaptive changes in renal structure and function that occur whenever renal function is reduced. These glomerular adaptations to renal disease include increases in filtration rate, capillary pressure and size, and are referred to as glomerular hyperfiltration, glomerular hypertension and glomerular hypertrophy, respectively. Extrarenal changes, such as dietary phosphate excess, systemic hypertension, hyperlipidaemia, acidosis and hyperparathyroidism occur in animals with renal disease and may be contributors to progression of renal disease. Emphasis in the management of companion animals with renal disease has shifted to identifying, understanding and controlling those processes that play a role in the progression from early to end-stage renal failure. Advances made by veterinary nephrologists in the past 15 years permit resolution of old controversies, formulation of new hypotheses and discussion of unresolved issues about the nature of progressive renal disease in dogs and cats.

Relationship between plasma iohexol clearance and urinary exogenous creatinine clearance in dogs.

The objective of this study was to determine if plasma iohexol clearance, computed by a 1-compartment model defined by 3 plasma samples. was an accurate measure of glomerular filtration rate (GFR) in dogs. Twenty-two adult Beagle dogs of both genders were studied. Ten dogs had intact kidneys, and 12 dogs had surgically reduced renal mass. A bolus injection of iohexol was made, and blood was obtained for plasma iohexol assay after 120, 180, and 240 minutes. Plasma was analyzed for iohexol concentration by means of 3 assay methods: chemical, high-performance liquid chromatography (HPLC), and inductively coupled plasma emission spectroscopy (ICP). Urinary clearance of exogenous creatinine was used to measure GFR for three 30-minute periods occurring between 150 and 240 minutes after iohexol injection. Plasma clearance of iohexol and renal clearance of creatinine were compared by linear regression analysis and by limits of agreement techniques. Plasma iohexol clearance and urinary exogenous creatinine clearance were significantly correlated (chemical R2 = .90; HPLC R2 = .96; and ICP R2 = .96). The 1-compartment iohexol clearance:exogenous creatinine clearance ratios were 1.04 +/- 0.17, 1.05 +/- 0.14, and 1.10 +/- 0.15 for the chemical, HPLC, and ICP methods of assay, respectively, indicating that plasma iohexol clearance slightly overestimated GFR. Assuming a +/- 2 standard deviation interval for error, corrected plasma iohexol clearance measured GFR with +/-34% accuracy for the chemical, +/-26% accuracy for the HPLC, and +/-27% accuracy for the ICP method. These results indicate that plasma iohexol clearance should have utility for detection of renal dysfunction earlier in the course of progressive renal disease than is possible with measurement of plasma creatinine or urea concentrations.

Effect of therapy on susceptibility to urinary tract infection in male cats with indwelling urethral catheters.

Indwelling urinary catheters with a closed urine collection system were maintained in 30 male cats for 3 days after induction of irritant cystitis. All cats received subcutaneous fluids during the 3 days the catheters were in place. The effects of four different treatment regimens on urinary tract infection rates, incidence of urethral obstruction, and development of urinary tract lesions over a 10-day period were compared with results in a nontreated group. Treatments were 1) amoxicillin for 5 days PO; 2) prednisolone for 5 days PO; 3) both amoxicillin and prednisolone for 5 days PO; and 4) dimethylsulfoxide (DMSO) for 3 days intravesicularly. Euthanasia was done before the end of the 10-day experimental period if the cats had two bouts of urethral obstruction or if the cats became uremic for causes unrelated to urethral obstruction. Seven cats were euthanatized before the conclusion of the experiment. These cats had been treated with prednisolone, prednisolone and amoxicillin, or DMSO. All cats that received amoxicillin alone or no therapy survived the 10-day period. Mortality was due to repeated urethral obstruction or to uremia associated with pyelonephritis or papillitis. Urinary tract infection rate was similar in all groups. The group treated with prednisolone alone had the highest incidence of renal infection. Inflammatory lesions in the lower urinary tract were similar in all groups. In conclusion, persistent urinary tract infection often develops in cats with cystitis after indwelling urethral catheterization even when closed systems of urine drainage are used.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of azathioprine versus cyclosporine on kidney graft survival in transfused and nontransfused unmatched mongrel dogs.

Sixteen mongrel dogs had bilateral nephrectomy and received a renal allograft from an unmatched mongrel. One group of eight dogs was treated orally with azathioprine and prednisone; another group of eight dogs was treated orally with cyclosporine and prednisone. Four dogs of each group received four blood transfusions each prior to surgery. Mean survival time was nearly the same in the azathioprine-treated and the cyclosporine-treated dogs. Transfusions prolonged survival in the azathioprine-treated group but not in the cyclosporine-treated group. Retrospective measurement of whole blood trough cyclosporine concentrations indicated marked variation between dogs and in the same dog at different times. This variation may have influenced graft survival. Only one dog survived the 9-month period of observation, indicating that refinements of the techniques used in this study will be required for long-term survival of renal allografts in unrelated mongrel dogs.

Relationship of lower urinary tract signs to seropositivity for feline immunodeficiency virus in cats.

A group of 41 cats with signs of lower urinary tract disease was compared to a group of 41 cats without any history of disease for prevalence of seropositivity for feline immunodeficiency virus (FIV). The group of healthy cats was similar in age and gender to the group of cats with signs of lower urinary tract disease. Three of the cats with lower urinary tract disease and one control cat were seropositive for FIV. This difference was not statistically significant. The most common cause of lower urinary tract signs was idiopathic. Only 7 cats had urinary tract infection, most associated with perineal urethrostomy or catheterization. Six of the cats with bacterial urinary tract infections were FIV negative.

Progression of chronic renal disease in the dog.

Progressive loss of nephron function may be caused by persistence of factors that initiated renal disease. However, newer studies suggest that nephron damage is self-perpetuating once renal mass is reduced to some critical level. Original theories on mechanisms of self-perpetuated nephron injury focused on intraglomerular hypertension and glomerular hypertrophy, but several other factors have now been incriminated, including tubulointerstitial responses, proteinuria, and oxidative stress. Studies of dogs with surgically reduced renal mass (remnant kidney model of chronic renal disease) have allowed investigation of the self-progression theory in this species. Use of this model eliminates pre-existing renal disease as a confounding factor. Data from these studies indicate that self-perpetuated renal injury is initiated when mild azotemia is induced (plasma creatinine concentration = 2 to 4 mg/dL). Thus, with naturally occurring renal disease(s), it is likely that self-perpetuated nephron damage is occurring before or at the time when most cases of chronic renal disease are diagnosed. In dogs with remnant kidneys, loss of renal function often occurs at a linear rate over time, but non-linear patterns are common as well. The reciprocal of plasma creatinine concentration, which has been used to monitor rate of progression, is only a fair marker of renal function when compared to GFR. Thus, clinical results from creatinine measurements on cases of naturally occurring disease should not be interpreted too stringently. In remnant kidney dogs, the magnitude of proteinuria (UPC ratio) was not predictive of the rate in decline of GFR, casting doubt on importance of proteinuria in causing progression of renal disease. However, progressive increases in UPC may be a marker of an accelerated rate of renal injury. Self-perpetuation of renal injury in dogs could be the sole mechanism by which naturally occurring renal diseases progress. When more information is available on the rate of progression of naturally occurring diseases, it may become apparent whether factors initially inciting renal damage have an additive effect on rate of progression.

Selective parathyroidectomy of the dog.

Selective parathyroidectomy (PTX) is preferred to thyroparathyroidectomy (TPTX) when specific effects of parathyroid hormone depletion are being studied. However, because of the anatomic proximity of thyroid and parathyroid glands, TPTX often is performed, leaving animals depleted of thyroxine (T4) and calcitonin as well as parathyroid hormone (PTH). In the present study, six normal dogs had parathyroid tissue and about seven-eighths of thyroid tissue removed. This quantity of thyroid tissue was inadequate to maintain normal serum T4 concentrations, despite allowance of 168 days for thyroid recovery. Five of six dogs with reduced renal mass had successful selective PTX and normal serum T4 concentrations at 28 days, when one-half or more of thyroid tissue was spared. We conclude that with attention to the surgical technique, selective PTX can be achieved in a high percentage of dogs and sufficient thyroid tissue spared to maintain euthyroidism.

Effects of dietary protein on glomerular mesangial area and basement membrane thickness in aged uninephrectomized dogs.

The primary objective of this study was to determine the effects of diets containing 18% or 34% protein on glomerular mesangial area (GMA) and basement membrane thickness (GBMT) in uninephrectomized aged dogs. A secondary objective was to determine the combined effects of aging and uninephrectomy on GMA and GBMT in dogs. Ten clinically healthy, pure-bred dogs were unilaterally nephrectomized at about 8 y of age. After 2 mo, 5 dogs were fed an 18% protein diet and 5 dogs were fed a 34% protein diet for 48 mo. At month 48, the dogs were euthanized and the remaining kidney was collected. Samples of kidney from both times of collection were used to measure GMA and GBMT using electron microscopy. The effects of diet on GMA and GBMT were analyzed (student's t-test) using necropsy/nephrectomy score ratios. The effects of time-nephrectomy were determined by comparing nephrectomy values for GMA and GBMT with necropsy values (paired t-test). Dogs fed 34% dietary protein did not have a significant increase in GMA and GBM thickness when compared to dogs fed the 18% protein diet. A significant increase in GMA and GBMT occurred with time-nephrectomy (P = 0.011 and 0.018, respectively). Although dietary protein intake was not a significant factor in causing structural changes to glomeruli in uninephrectomized aged dogs, the power to detect a difference was low. However, significant effects of aging and nephrectomy were detected despite the low power of the study. These results suggest that the increases in GMA and GBMT that occur over time are not markedly influenced by dietary protein intake. However, subtle protein effects cannot be eliminated as a possibility based on this study.

Efficacy of ethylenediamine dihydrochloride in dogs and cats.

Ethylenediamine dihydrochloride was administered to dogs and cats with induced Escherichia coli urinary tract infections and to clinically normal dogs and cats to determine if the drug had diuretic, antibacterial, or urinary acidification properties. In dogs, the drug had no diuretic or antibacterial properties and did not modify the postprandial production of alkaline urine. In cats, the drug had no diuretic or antibacterial properties, but caused a slight reduction in urine pH when multiple doses were administered. Ethylenediamine dihydrochloride appeared to have no value in the treatment of E coli urinary infection under the conditions of the present study.

Familial renal disease in Norwegian Elkhound dogs: physiologic and biochemical examinations.

Renal disease was detected in 21 of 56 progeny from a specific line of inbred Norwegian Elkhound (NE) dogs. Results of hematologic and clinical chemistry examinations revealed that minor differences existed between affected and nonaffected NE dogs. Of 21 NE dogs with renal disease, 3 had persistent glucosuria without hyperglycemia. The 21 affected dogs had impaired ability to concentrate urine. According to renal function tests, glomerular filtration rate of normal NE dogs was less than that of normal mixed breed dogs. Although a few affected NE dogs excreted large amounts of amino acids in urine, statistically significant differences did not exist between normal and affected NE dogs with regard to alpha-amino acid nitrogen content of their plasma or urine. By paper chromatographic separation techniques, free amino acids of plasma, urine, and extracts of liver and kidney were not qualitatively different for mixed breed dogs, normal NE, and NE with renal disease. Statistically significant differences were not detected between serum calcium concentrations of normal and affected NE dogs. In NE dogs with renal disease, there was significant hypercalciuria, but a few normal dogs excreted more than did some dogs with disease. Blood pressure values of normal mixed breed dogs and affected NE dogs were similar. It was concluded that hematologic and blood chemical abnormalities, derangement of amino acid or calcium metabolism, and hypertension were not associated with renal disease in these NE dogs.

Characterization of the renal response to protein ingestion in dogs with experimentally induced renal failure.

Effects of a protein meal (2.7 g of casein/kg of body weight) on glomerular filtration rate (GFR) and renal plasma flow (RPF) were assessed in dogs after 15/16 nephrectomy (n = 10), and were compared with observations in dogs with intact kidneys (n = 5). Increase in GFR and RPF was observed in both groups of dogs between 1.5 and 8 hours after protein ingestion. A maximal value for GFR was observed between 4 and 5 hours after protein ingestion in dogs of both groups. Enhancement of urinary protein excretion was evident in partially nephrectomized dogs after protein ingestion (P less than 0.05), a result that was confirmed by 24-hour total urine collection from partially nephrectomized dogs fed a balanced ration. A qualitatively similar vasodilatory response was observed in partially nephrectomized dogs and in dogs with intact kidneys, and the mean maximal increase of GFR and RPF expressed as a percentage of baseline values in the latter dogs (47.0 +/- 8.1 and 43.6 +/- 10.3%, respectively) exceeded that observed in partially nephrectomized dogs (20.8 +/- 2.2 and 22.7 +/- 6.3%, respectively; P less than 0.01). The incremental response of the kidneys to protein ingestion was directly related to the degree of renal function, as reflected in the linear regression relationship between the incremental increase in GFR and the baseline value for GFR (P less than 0.01, R2 = 0.721).

Frequency of pyelitis, pyelonephritis, renal perivasculitis, and renal infarction in dogs.

The frequency of pyelitis, renal perivasculitis, and renal cortical inflammation was determined in 104 apparently normal dogs, 50 dogs with disease that were necropsied, and 20 dogs with experimentally induced cystitis. Abnormalities occurred least often (19%) in the apparently normal group and most often (55%) in the cystitis group. The frequency of specific lesions was generally higher in males than in females. Bacteria were isolated from kidney and urine of some of the apparently normal dogs, but their relationship to the lesions observed was not established.

Relationship of selected clinical renal function tests to glomerular filtration rate and renal blood flow in cats.

Results of 3 clinical tests of renal function--urine concentrating ability and disappearance of plasma phenosulfonphthalein (PSP) and sodium sulfanilate (SS) were compared with those of 2 classic tests, glomerular filtration rate (GFR) and renal blood flow (RBF), in 11 cats before and after reduction of renal mass. Values (mean +/- SD) obtained from normal cats were maximum urine concentration of 2,270 +/- 407 mOsm/kg (specific gravity values of 1.067 +/- 0.015); T 1/2 for plasma disappearance of PSP of 24.27 +/- 3.5 minutes; T 1/2 for plasma disappearance of SS of 44.42 +/- 5.67 minutes; GFR of 2.94 +/- 0.32 ml/min/kg; and RBF of 10.61 +/- 1.71 ml/min/kg. After reduction of renal mass by vascular ligation and nephrectomy, the cats became azotemic and had significant decreases in GFR and RBF (P less than 0.005), but still were able to concentrate urine to a considerable extent. Both maximum urine concentration and PSP plasma decay were poorly correlated with GFR (r = 0.4060 and 0.3694, respectively) and RBF (r = -0.3439 and -0.3427). Sulfanilate half-life had better correlation with GFR (r = -0.7004) than with RBF (r = -0.5716). Both GFR and RBF increased significantly (P less than 0.005) between postsurgical weeks 1 and 9. It was concluded that experimental cats with azotemia retain considerable ability to concentrate urine and that the SS test is superior to both the PSP test and urine concentration test for clinical estimation of renal function.

Mechanism of urinary excretion of creatinine by the cat.

Creatinine and [14C]inulin clearance values were nearly the same during stop-flow and free-flow conditions in the cat. We conclude that glomerular filtration is the sole factor in renal excretion of creatinine in this species. Anatomic (bladder vs kidney) and dynamic (slow vs fast urine flow rate) studies indicated insignificant changes occurred in creatinine content of urine as it traversed the ureter and bladder of cats. We conclude that the cat ureter and bladder under conditions of moderate distension are relatively impermeable to creatinine.

Characterization and treatment of water, electrolyte, and acid-base imbalances of induced urethral obstruction in the cat.

Urethral obstruction induced in adult male cats caused clinical signs identical with those observed in naturally occurring disease. Central nervous system depression, anorexia, dehydration, vomiting, muscle weakness, and hypothermia occurred. Weight loss (due to water loss and catabolism), metabolic acidosis, mild hyponatremia, hyperkalemia, hypermagnesemia, hypocalcemia, hyperphosphatemia, hyperglycemia, azotemia, and hyperproteinemia were also observed. Serum amylase, alkaline phosphatase, and alanine aminotransferase activities were normal. Ten of 13 cats (group 1), with 72 hours' induced obstruction but not treated with parenteral fluids, died either before the obstruction was relieved or within 8 days afterward. Eight cats (group 2) with induced obstruction for 49 to 98 hours developed severe clinical and biochemical alterations. Treatment with a multiple-electrolyte solution, in addition to relief of urethral obstruction, resulted in favorable clinical and biochemical responses. These cats survived and were clinically healthy at 9 to 10 days after relief of obstruction. It was concluded that use of a multiple-electrolyte solution to correct acidosis, restore circulatory volume, and enhance renal excretion of potassium was effective supportive therapy after urethral obstruction was removed.

Mechanism of renal excretion of creatinine by the pony.

Free-flow and stop-flow procedures conducted on 2 female and 2 testosterone-treated castrated male ponies indicated that [14C]inulin and exogenous creatinine clearance values were the same. These results indicated that creatinine was neither reabsorbed nor secreted by the renal tubules and that exogenous creatinine clearance was an accurate method for determining glomerular filtration rate. As in other species which have been studied, endogenous creatinine clearance probably underestimated glomerular filtration rate because of the presence of noncreatinine chromogens in plasma.

Effect of atropine on cystometry and urethral pressure profilometry in the dog.

Effects of atropine on cystometry and urethral pressure profilometry were examined in 12 healthy young adult dogs by comparing recordings obtained after xylazine alone with those obtained after administration of xylazine and atropine. Significant differences (P greater than 0.05) were not found, indicating that atropine, when administered SC with xylazine, did not markedly affect cystometrographic results and urethral pressure profiles.

Use of plasma clearance of inulin for estimating glomerular filtration rate in cats.

OBJECTIVE: To evaluate utility of a method for estimating glomerular filtration rate after a single i.v. injection of inulin. ANIMALS: Cats that were renal intact (n = 3) or had renal mass reduced by partial nephrectomy (n = 6). PROCEDURE: Plasma clearance of inulin (PCln) was taken as the quotient of the administered dose of inulin (150 mg) divided by the area under the plasma inulin concentration versus time curve determined by 3 methods (PCln1-PCln3). Results for PCln were compared with simultaneously obtained values for urinary clearance of exogenous creatinine (CCr), an accepted method for the estimation of glomerular filtration rate (GFR) in cats. RESULTS: Values for PCln were closely related (R2 ranged from 0.951 to 0.972, P < 0.0001 in all instances) to CCr. However, PCln3 provided an estimate of GFR that consistently overestimated CCr. CONCLUSION: Determination of PCln by use of PCln1 and PCln2 provided a reliable estimate of GFR in cats of this study. CLINICAL RELEVANCE: Determination of PCln appears to provide a reliable estimate of GFR in cats with early-stage renal disease and no evidence of derangement of body fluid status. In particular, PCln2, which requires only 3 determinations of plasma inulin concentration, should be considered when an estimate of GFR is sought in a cat with suspected early-stage renal disease.

Endogenous creatinine clearance measurement of glomerular filtration rate in dogs.

Renal clearance procedures were performed on adult mixed-breed dogs with a wide range of renal function. Endogenous creatinine clearance was computed after analyzing plasma and urine for creatinine by use of 2 methods, PAP and kinetic Jaffe. For 20-minute clearance procedures, [14C]inulin clearance was measured simultaneously with endogenous creatinine clearance. For 111 twenty-minute clearance procedures performed on 24 dogs, [14C]inulin clearance was highly correlated with creatinine clearance for both methods of creatinine analysis (R2 = 0.979 for [14C]inulin-PAP; R2 = 0.943 for [14C]inulin-Jaffe). The absolute values for PAP and [14C]inulin clearance were nearly the same (PAP-to-[14C]inulin clearance ratio = 1.03 +/- 0.08), but those for Jaffe clearance were substantially less than those for [14C]inulin clearance (Jaffe-to-[14C]inulin clearance ratio = 0.88 +/- 0.10). The Jaffe-to-[14C]inulin clearance ratio was inversely correlated with degree of renal function (R2 = 0.464), whereas the PAP-to-[14C]inulin clearance ratio was not correlated with degree of renal function (R2 = 0.060). Thus, Jaffe-determined creatinine clearance varied, in relation to [14C]inulin clearance, depending on degree of renal function. In 4 clinically normal dogs, 20-minute and 24-hour sample collections analyzed by use of the PAP method gave clearance values significantly greater, for both periods, than did Jaffe analyses. The PAP-determined creatinine clearance values were less than, but not significantly different from 20-minute exogenous creatinine clearance values determined 10 days after 24-hour collections.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of hydration state on renal functions of dogs.

Clinically normal dogs were evaluated in states of dehydration, euhydration, and after fluid administration to determine effects of hydration state on renal clearance values. Endogenous creatinine, exogenous creatinine, and [14C]inulin clearances, were determined to measure glomerular filtration rate (GFR); in some experiments p-aminohippurate clearance was determined to measure renal plasma flow. Dehydration caused significant (P < 0.05) decrease in clearance values, compared with euhydration, and clearance values during euhydration were significantly (P < 0.05) less than values obtained after a single gavage with water (30 ml/kg of body weight). Sustained administration of 3 fluid regimens was evaluated for effects on clearance values (treatment A = 30 ml of lactated Ringer's solution/kg/h; treatment B = 30 ml of water/kg by gavage hourly; treatment C = 10 ml of glucose:lactated Ringer's solution/kg/h). All regimens of fluid therapy caused significant P < 0.05), progressive increases in GFR, but treatment C resulted in the most stable GFR values. Increases in clearance values were associated with positive fluid balance; the rate of fluid administration was greater than the rate of urine formation. Data from 285 GFR determinations on 85 dogs were evaluated retrospectively. For each determination, three 20-minute urine collections were made beginning 40 minutes after 30 ml of water/kg was given by gavage. Values between collections were significantly (P < 0.05) different, but varied by < 3%. Comparison of methods for measurement of GFR indicated that endogenous creatinine clearance and [14C]inulin clearance were highly correlated (R2 = 0.82), but mean clearance values were markedly different (mean +/- SEM, 28.70 +/- 0.01 and 37.07 +/- 1.29 ml/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)