Polycystic kidney disease: new horizons and therapeutic frontiers.

Autosomal dominant polycystic kidney disease (ADPKD) represents the most prevalent inherited kidney disease, and an important contributor to renal and systemic morbidity. Almost 20 years after the discovery of the Pkd-1 and Pkd-2 genes, the exact molecular mechanisms of polycystic kidney disease pathogenesis still remain elusive. In the absence of a specific therapy for polycystic kidney disease, patients are treated for chronic kidney disease symptoms, like hypertension, anemia, hyperparathyroidism and pain. Intensive research on ADPKD and a variety of related complex cystic kidney disease syndromes revealed a network of intracellular signaling pathways that depend on ciliary function and include calcium- and cAMP-dependent mechanisms. Furthermore, proliferative and tissue patterning responses to mTOR, STAT, CDK and wnt signaling play an important role in various aspects of cystogenesis and represent further targets for therapy. Only a limited amount of clinical evidence from randomized controlled trials is currently available to evaluate treatment options. This includes ongoing trials of the vasopressin receptor-2 antagonist tolvaptan, as well as a set of studies that fail to show a clear therapeutic benefit of everolimus or sirolimus in PKD progression. Future research will involve the evaluation of small molecule inhibitors of growth factor receptor-, CDK- and STAT-pathways, as well as the characterization of novel biomarkers of disease progression and therapeutic response.

Pain management in polycystic kidney disease.

Pain is a common complaint in patients with autosomal-dominant polycystic kidney disease, and a systematic approach is needed to differentiate the etiology of the pain and define an approach to management. A thorough history is the best clue to the multifactorial causes of the pain, superimposed upon an understanding of the complex innervation network that supplies the kidneys. The appropriate use of diagnostic radiology (especially MRI) will assist in differentiating the mechanical low back pain caused by cyst enlargement, cyst rupture and cyst infection. Also, the increased incidence of uric acid nephrolithiasis as a factor in producing renal colic must be considered when evaluating acute pain in the population at risk. MRI is not a good technique to detect renal calculi, a frequent cause of pain in polycystic kidney disease. If stone disease is a possibility, then abdominal CT scan and/or ultrasound should be the method of radiologic investigation. Pain management is generally not approached in a systematic way in clinical practice because most physicians lack training in the principles of pain management. The first impulse to give narcotics for pain relief must be avoided. Since chronic pain cannot be "cured," an approach must include techniques that allow the patient to adapt to chronic pain so as to limit interference with their life style. A detailed stepwise approach for acute and chronic pain strategies for the patient with autosomal dominant polycystic kidney disease is outlined.

Guidelines for the referral and management of patients eligible for solid organ transplantation.

Members of the Clinical Practice Committee, American Society of Transplantation, have attempted to define referral criteria for solid organ transplantation. Work done by the Clinical Practice Committee does not represent the official position of the American Society of Transplantation. Recipients for solid organ transplantation are growing in numbers, progressively outstripping the availability of organ donors. As there may be discrepancies in referral practice and, therefore, inequity may exist in terms of access to transplantation, there needs to be uniformity about who should be referred to transplant centers so the system is fair for all patients. A review of the literature that is both generic and organ specific has been conducted so referring physicians can understand the criteria that make the patient a suitable potential transplant candidate. The psychosocial milieu that needs to be addressed is part of the transplant evaluation. Early intervention and evaluation appear to play a positive role in maximizing quality of life for the transplant recipient. There is evidence, especially in nephrology, that the majority of patients with progressive failure are referred to transplant centers at a late stage of disease. Evidence-based medicine forms the basis for medical decision-making about accepting the patient as a transplant candidate. The exact criteria for each organ are detailed. These guidelines reflect consensus opinions, synthesized by the authors after extensive literature review and reflecting the experience at their major transplant centers. These guidelines can be distributed by transplant centers to referring physicians, to aid them in understanding who is potentially an acceptable candidate for transplantation. The more familiar physicians are with the exact criteria for specific organ transplantation, the more likely they are to refer patients at an appropriate stage. Individual transplant centers will make final decisions on acceptability for transplantation based on specific patient factors. It is hoped that this overview will assist insurers/payors in reimbursing transplant centers for solid organ transplantation, based on criteria for acceptability by the transplant community. The selection and management of patients with end-stage organ failure are constantly changing, and future advances may make obsolete some of the criteria mentioned in the guidelines. Most importantly, these are intended to be guidelines, not rules.

Evaluation of disease-state management of dialysis patients.

Dialysis patients are the only Medicare beneficiaries prohibited from joining managed care plans. Concerns have been raised about the ability of such plans to provide the comprehensive care required by patients with this complex condition. However, more than 20,000 dialysis patients belong to such plans because they were enrolled before developing end-stage renal disease (ESRD). Disease-state management, successfully applied to patients with diabetes mellitus and congestive heart failure, is now being used in patients with ESRD. Standardized mortality ratios (SMRs) and standardized hospitalization ratios (SHRs) were calculated for 1998 and 1999 in 1,541 patients enrolled in the RMS Disease Management program of renal disease-state management using US Renal Data System methods. SMRs were 0.643 and 0.806 for 1998 and 1999, respectively, significantly different from 1.0 for both years (P < 0.001). SHRs were 0.620 and 0.503 for 1998 and 1999, respectively, significantly different from 1.0 for both years (P < 0.001). Although additional studies are needed to define the aspects of care that are most important for the outcomes seen, this study shows that favorable outcomes are achievable for this vulnerable patient population within a managed care setting that applies coordinated approaches to care.

Serum albumin: its significance in patients with ESRD.

Hypoalbuminemia is a major risk factor for morbidity and mortality in the ESRD population. The Core Indicators Project notes that the serum albumin value is a measure of the patient's nutritional status. Since 1994 every outcome parameter of the Core Indicators Project has shown improvement except for the serum albumin measurement. While the serum albumin level is a measure of the visceral protein pool size, a decrease in albumin synthesis is due to more than poor nutritional intake (in part related to inadequate dialysis). Acute-phase reactants and the plasma volume status are other major factors that impact on serum albumin determination. Plasma volume expansion, albumin redistribution, exogenous loss (in peritoneal dialysis patients), and decreased albumin synthesis all contribute to hypoalbuminemia. Understanding the cause (s) of hypoalbuminemia will allow us to target treatment modalities directed at correcting the hypoalbuminemia. It is still unknown if the serum albumin can be effectively raised in the chronic dialysis patient. Also unknown is whether an increase in the serum albumin level can alter long-term morbidity and mortality. We should not be using serum albumin as an indicator of adequate dialysis or nutritional status since the causes ofhypoalbuminemia are multifactorial. It is recommended that the serum albumin level be eliminated as an indicator of nutritional status in the ESRD patient.

Effect of a ketoacid-aminoacid-supplemented very low protein diet on the progression of advanced renal disease: a reanalysis of the MDRD feasibility study.

BACKGROUND: We reanalyzed the data of the Modification of Diet in Renal Disease (MDRD) feasibility study to ascertain the effects of ketoacid- and aminoacid-supplemented very low protein diets. METHODS: Sixty-six patients with advanced renal disease (Study B, baseline glomerular filtration rate (GFR) 7.5-24 ml/min/1.73 m2) were randomly assigned to a low protein diet (L, 0.575 g/kg/d), or a very low protein diet (0.28 g/kg/d) supplemented either with a ketoacid-aminoacid mixture (diet K) or with a mixture of essential aminoacids (diet J). Thirty patients with moderate renal disease (Study A, baseline GFR 25-80 ml/min/1.73 m2) were randomly assigned to a usual protein diet (M, 1.2 g/kg/d), diet L, or diet K. Mean follow-up was 14 months. RESULTS: In Study B, GFR decline differed among the three diets (p = 0.028). Pairwise comparisons showed that the mean +/- SE GFR decline in ml/min/mo in diet K [-0.250+/-0.072] was slower than in diet J [-0.533+/-0.074] (p = 0.008) despite similar achieved protein intakes. The mean GFR decline in diet L [-0.394+/-0.068] was intermediate between, and did not differ significantly from the rates of decline in the other two groups. In Study A, consistent with a hemodynamic effect, the mean GFR decline varied directly with the reduction in protein intake in diets M, L and K (p = 0.028) during the first four months of follow-up, but thereafter did not differ among the diet groups (p = 0.76). CONCLUSION: The study suggests that supplementation of a very low protein diet with the ketoacid-aminoacid mixture used in this feasibility study slowed the progression of advanced renal disease more than supplementation with an amino acid mixture.

Managed care, capitation, and the future of nephrology.

Within the next decade, it is predicted that more than 90% of the United States population will receive its health insurance through managed care. Capitation will be the reimbursement mechanism to health care providers as the major way of controlling costs. Currently, managed care has had little experience with capitation payments for chronically ill patients, who consume large financial and physical resources. The end-stage renal disease (ESRD) population represents a vulnerable group of patients, and their care may be compromised in a capitated environment. Nephrologists will need to serve as advocates for ESRD patients through a mechanism of quality of care, driven by a continuous quality improvement model. Cost-effective delivery of care will occur as nephrologists join together to form Independent Practice Associations (IPAs). In this article, the role of a nephrologist in a capitated environment is outlined in detail, and background for the basis of managed care growth is provided as a framework for understanding the change in our health care delivery system. After formation of a nephrology IPA, there will most likely be a linkage with a management service organization (MSO). A business plan driven by the highest principles will allow nephrologists to work together as a cohesive force in accepting global risk capitated contracts. The starting point is for ESRD care, and the future includes pre-ESRD care.

The dialysis facility of the future: the financial and social environment.

Changes in the delivery of care are being driven by the rapid advance of managed care. Nephrologists must continue to be advocates for the end-stage renal disease (ESRD) patient in a medical environment obsessed with costs. Reorganization of nephrology will be mandatory because capitation is on the immediate horizon. Fee-for-service care will diminish, and nephrologists must learn how to become the driving force for quality care in a cost-effective environment. The formation of nephrology Independent Practice Associations (IPAs) will create the structure that allows nephrologists to negotiate and accept global captitated contracts for ESRD care. Placing the patients' interests first will ultimately lead to reduced costs. Changes in the nephrology workforce over the next decade will dictate participation in a horizontal and vertical integration team approach to care of the patient with ESRD.

Combined gastric and ileocecal toxicity (serpiginous ulcers) after oral kayexalate in sorbital therapy.

Kayexalate (Roxane Labs, Columbus, OH) in sorbitol is commonly administered by the oral and rectal route for the treatment of hyperkalemia in patients with renal failure. It is believed to have minimal toxicity because it functions as a cation exchanger and is not absorbed. We herein report on a patient who developed identical serpiginous ulcers in the stomach and the terminal ileum after the use of Kayexalate. We believe that this drug could have significant gastrointestinal toxicity in specific patient groups and suggest tentative guidelines, both for the identification of such patients and for the safer use of Kayexalate in these circumstances.

Kidney protection: how to prevent or delay chronic renal failure.

In patients at risk for chronic renal failure, early clinical interventions have been shown to prevent or delay progression of the disease. A low-protein diet is recommended when the serum creatinine is between 1.5 and 2.5 mg/dl. Benefit from protein restriction can only be achieved if energy intake is greater than 35 kcal/kg/d. To preserve skeletal muscle, correct metabolic acidosis with oral sodium bicarbonate supplementation. For hypertension control and renal protection, start ACE inhibitors when serum creatinine is less than 2 mg/dl. Correct anemia with erythropoietin to improve or maintain quality of life when the hematocrit falls below 30%. For the diabetic, ACE inhibitors and glycemic control have been shown to show the rate of renal failure.

Contrast-induced encephalopathy and seizures in a patient with chronic renal insufficiency.

Radiographic contrast agents are associated with a number of adverse effects, including central nervous system effects and seizures. Almost all contrast agents are primarily filtered and excreted by the kidneys, and they accumulate in patients with end-stage renal disease. Brain retention of contrast associated with high doses is a rare event, having been reported only twice in the literature. We report a case of a 49-year-old male on chronic hemodialysis who developed brain retention of contrast resulting in seizures and encephalopathy after receiving large doses of meglumine/sodium diatrizoate during coronary angiography. He was treated successfully with hemodialysis and suffered no permanent neurologic sequelae. Patients with end-stage renal disease may be at increased risk of adverse effects from contrast when administered in high doses.

Clarithromycin-associated visual hallucinations in a patient with chronic renal failure on continuous ambulatory peritoneal dialysis.

Visual hallucinations are a rare event in chronic renal failure and not related to uremia per se. Unreported in the literature is visual hallucinations occurring in association with the new macrolide antibiotic, clarithromycin. We describe such a case in a patient with end-stage renal disease (ESRD) maintained on continuous ambulatory peritoneal dialysis (CAPD). The combination of a relatively high dose of clarithromycin in face of chronic renal failure in a functionally anephric patient, with underlying aluminum intoxication, may have facilitated the appearance of this neurotoxic side effect. It is important to understand the pharmacokinetics of medications in face of chronic renal failure, the possibility of drug interactions, and how these factors should help guide medication therapy in the ESRD patient.

Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease. Modification of Diet in Renal Disease Study Group.

In the Modification of Diet in Renal Disease Study, a follow-up (mean, 2.2 yr) of 200 study participants with autosomal dominant polycystic kidney disease (ADPKD) was conducted to determine the effect of lowering protein intake and blood pressure on the rate of decline in GFR. The rate of decline was faster in participants with ADPKD than in persons with other diagnoses, reflecting, in part, faster disease progression in the ADPKD group. Baseline characteristics that predicted a faster rate of decline in GFR in persons with ADPKD were greater serum creatinine (independent of GFR), greater urinary protein excretion, higher mean arterial pressure (MAP), and younger age. In patients with initial GFR values between 25 and 55 mL/min per 1.73 m2, neither assignment to a low-protein diet group nor assignment to a low blood pressure group significantly reduced the rate of decline of GFR in ADPKD participants. Similarly, the decline in GFR was not related to achieved protein intake or MAP. In participants with GFR values between 13 and 24 mL/min per 1.73 m2, assignment to the low MAP group led to a somewhat more rapid decline in GFR. However, the more rapid decline in GFR did not appear to be due to a detrimental effect of low blood pressure or the antihypertensive agents used to reach the low blood pressure goal. Lower protein intake, but not prescription of the keto acid-amino acid supplement, was marginally associated with a slower progression of renal disease.

Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients.

A study was undertaken to ascertain the effects of recombinant human erythropoietin (r-HuEPO) on renal function in chronic renal failure predialysis patients. The effect of improvement of anemia by r-HuEPO on the rate of decline in renal function in predialysis patients has not been previously studied prospectively in a large number of patients using reliable measures of glomerular filtration rate (GFR). To investigate the efficacy, safety, and impact of r-HuEPO therapy in chronic renal insufficiency patients, a 48-week, randomized, open-label, multicenter study was initiated in 83 anemic, predialysis (serum creatinine 3 to 8 mg/dL) patients. Serial GFRs were measured using 125I-iothalamate clearance. Forty patients were randomized to the untreated arm and 43 patients to the treatment arm (50 U/kg r-HuEPO subcutaneously three times weekly). Baseline characteristics were comparable for the r-HuEPO-treated and untreated groups. During this 48-week study, GFR, mean arterial blood pressure, and daily protein intake were not significantly different between the two groups. There was a statistically significant increase in hematocrit for the r-HuEPO-treated group that was not associated with acceleration of deterioration in residual renal function. This was demonstrated by the lack of a significant (P = 0.376) between-group difference in mean change in GFR from baseline to last available value for the r-HuEPO-treated (-2.1 +/- 3.2 mL/min) and untreated (-2.8 +/- 3.5 mL/min) groups. This study concludes that r-HuEPO therapy improves anemia in predialysis patients and does not accelerate the rate of progression to end-stage renal disease.